Substituted amides

ABSTRACT

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson&#39;s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

BACKGROUND OF THE INVENTION

Marijuana (Cannabis sativa L.) and its derivatives have been used forcenturies for medicinal and recreational purposes. A major activeingredient in marijuana and hashish has been determined to beΔ⁹-tetrahydrocannabinol (Δ⁹-THC). Detailed research has revealed thatthe biological action of Δ⁹-THC and other members of the cannabinoidfamily occurs through two G-protein coupled receptors termed CB1 andCB2. The CB1 receptor is primarily found in the central and peripheralnervous systems and to a lesser extent in several peripheral organs. TheCB2 receptor is found primarily in lymphoid tissues and cells. Threeendogenous ligands for the cannabinoid receptors derived fromarachidonic acid have been identified (anandamide, 2-arachidonoylglycerol, and 2-arachidonyl glycerol ether). Each is an agonist withactivities similar to Δ⁹-THC, including sedation, hypothermia,intestinal immobility, antinociception, analgesia, catalepsy,anti-emesis, and appetite stimulation.

The genes for the respective cannabinoid receptors have each beendisrupted in mice. The CB1^(−/−) receptor knockout mice appeared normaland fertile. They were resistant to the effects of Δ⁹-THC anddemonstrated a strong reduction in the reinforcing properties ofmorphine and the severity of withdrawal syndrome. They also demonstratedreduced motor activity and hypoalgesia. The CB2^(−/−) receptor knockoutmice were also healthy and fertile. They were not resistant to thecentral nervous system mediated effects of administered Δ⁹-THC. Therewere some effects on immune cell activation, reinforcing the role forthe CB2 receptor in immune system functions.

Excessive exposure to Δ⁹-THC can lead to overeating, psychosis,hypothermia, memory loss, and sedation. Specific synthetic ligands forthe cannabinoid receptors have been developed and have aided in thecharacterization of the cannabinoid receptors: CP55,940 (J. Pharmacol.Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther.1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; LifeSci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999,288, 582-589). The pharmacology and therapeutic potential forcannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents1998, 8, 301-313; Ann. Rep. Med. Chem, A. Doherty, Ed.; Academic Press,NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538;Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB1modulator characterized as an inverse agonist or an antagonist,N-(1-piperidinyl)-5-(4-chlorophenyl)-1-2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide(SR141716A), in clinical trials for treatment of eating disorders atthis time. There still remains a need for potent low molecular weightCB1 modulators that have pharmacokinetic and pharmacodynamic propertiessuitable for use as human pharmaceuticals.

Treatment of asthma with CB1 receptor modulators (such as CB1 inverseagonists) is supported by the finding that presynaptic cannabinoidCB1-receptors mediate the inhibition of noradrenaline release (in theguinea pig lung) (Europ. J. of Pharmacology, 2001, 431 (2), 237-244).

Treatment of cirrhosis of the liver with CB1 receptor modulators issupported by the finding that a CB1 receptor modulator will reverse thelow blood pressure observed in rats with carbon tetrachloride-inducedliver cirrhosis and will lower the elevated mesenteric blood flow andportal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).

U.S. Pat. No. 5,624,941 and U.S. Pat. No. 6,028,084, PCT ApplicationNos. WO98/31227, WO98/41519, WO98/43636, WO98/43635 and WO 02/076949,and EPO Application No. EP-658546 disclose substituted pyrazoles havingactivity against the cannabinoid receptors.

PCT Application Nos. WO98/37061, WO00/10967, and WO00/10968 disclosediaryl ether sulfonamides having activity against the cannabinoidreceptors.

PCT Application Nos. WO97/29079 and WO99/02499 disclosealkoxy-isoindolones and alkoxy-quinolones as having activity against thecannabinoid receptors.

U.S. Pat. No. 5,532,237 discloses N-benzoyl-indole derivatives havingactivity against the cannabinoid receptors.

U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat. No.5,081,122, and U.S. Pat. No. 5,112,820, U.S. Pat. No. 5,292,736 discloseaminoalkylindole derivatives as having activity against the cannabinoidreceptors.

PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazolecannabinoid receptor modulators useful for treating respiratory andnon-respiratory leukocyte activation-associated disorders.

PCT publications WO 01/64632, 01/64633, and 01/64634 are directed toazetidine derivatives as cannabinoid antagonists.

Schultz, E. M., et al. J. Med. Chem 1967, 10, 717 and Pines, S. H. etal. J. Med. Chem. 1967, 10, 725 disclose maleamic acids affecting plasmacholesterol and penicillin excretion.

The compounds of the present invention are modulators of theCannabinoid-1 (CB1) receptor and are useful in the treatment, preventionand suppression of diseases mediated by the Cannabinoid-1 (CB1)receptor. In particular, compounds of the present invention areantagonists or inverse agonists of the CB1 receptor. The invention isconcerned with the use of these compounds to modulate the Cannabinoid-1(CB1) receptor. As such, compounds of the present invention are usefulas centrally acting drugs in the treatment of psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, neuro-inflammatorydisorders including multiple sclerosis and Guillain-Barre syndrome andthe inflammatory sequelae of viral encephalitis, cerebral vascularaccidents, and head trauma, anxiety disorders, stress, epilepsy,Parkinson's disease, movement disorders, and schizophrenia. Thecompounds are also useful for the treatment of substance abusedisorders, particularly to opiates, alcohol, marijuana, and nicotine.The compounds are also useful for the treatment of eating disorders byinhibiting excessive food intake and the resulting obesity andcomplications associated therewith. The compounds are also useful forthe treatment of constipation and chronic intestinal pseudo-obstruction,as well as for the treatment of asthma, and cirrhosis of the liver.

SUMMARY OF THE INVENTION

The present invention is concerned with novel substituted amides of thegeneral Formula I:

and pharmaceutically acceptable salts thereof which are antagonistsand/or inverse agonists of the Cannabinoid-1 (CB1) receptor and areuseful in the treatment, prevention and suppression of diseases mediatedby the Cannabinoid-I (CB1) receptor. The invention is concerned with theuse of these novel compounds to selectively antagonize the Cannabinoid-1(CB1) receptor. As such, compounds of the present invention are usefulas centrally acting drugs in the treatment of psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, neuro-inflammatorydisorders including multiple sclerosis and Guillain-Barre syndrome andthe inflammatory sequelae of viral encephalitis, cerebral vascularaccidents, and head trauma, anxiety disorders, stress, epilepsy,Parkinson's disease, movement disorders, and schizophrenia. Thecompounds are also useful for the treatment of substance abusedisorders, particularly to opiates, alcohol, marijuana, and nicotine,including smoking cessation. The compounds are also useful for thetreatment of obesity or eating disorders associated with excessive foodintake and complications associated therewith. The compounds are alsouseful for the treatment of constipation and chronic intestinalpseudo-obstruction. The compounds are also useful for the treatment ofcirrhosis of the liver. The compounds are also useful for the treatmentof asthma.

The present invention is also concerned with treatment of theseconditions, and the use of compounds of the present invention formanufacture of a medicament useful in treating these conditions. Thepresent invention is also concerned with treatment of these conditionsthrough a combination of compounds of formula I and other currentlyavailable pharmaceuticals.

The invention is also concerned with novel compounds of structuralformula I. The invention is also concerned with pharmaceuticalformulations comprising one of the compounds as an active ingredient.

The invention is further concerned with processes for preparing thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds used in the methods of the present invention arerepresented by the compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein;R¹ is selected from:

-   -   (1) aryl,    -   (2) aryl-C₁₋₄alkyl,    -   (3) heteroaryl,    -   (4) heteroaryl-C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a), and each aryl        and heteroaryl are optionally substituted with one to four        substituents independently selected from R^(b);        R² is selected from:    -   (1) C₁₋₁₀alkyl,    -   (2) C₃₋₁₀cycloalkyl-C₁₋₄alkyl,    -   (3) cycloheteroalkyl,    -   (4) cycloheteroalkyl-C₁₋₄alkyl,    -   (5) aryl,    -   (6) aryl-C₁₋₄alkyl,    -   (7) heteroaryl, and    -   (8) heteroaryl-C₁₋₄yl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a), and each        cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally        substituted with one to four substituents independently selected        from R^(b);        R³ is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a);        R⁴ is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₄alkyl,    -   wherein each alkyl is optionally substituted with one to four        substituents independently selected from R^(a);        R⁵ is selected from:    -   C₁₋₁₀alkyl,    -   (2) C₂₋₁₀alkenyl,    -   (3) C₃₋₁₀cycloalkyl,    -   (4) C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,    -   (5) cycloheteroalkyl-C₁₋₁₀alkyl,    -   (6) aryl-C₁₋₁₀alkyl,    -   (7) diaryl-C₁₋₁₀alkyl,    -   (8) aryl-C₂₋₁₀alkenyl,    -   (9) heteroaryl-C₁₋₁₀alkyl,    -   (10) —R^(d), and    -   (11) —NR^(c)R^(d),    -   wherein alkyl, alkenyl cycloalkyl, and cycloheteroalkyl are        optionally substituted with one to four substituents        independently selected from R^(a) and cycloalkyl,        cycloheteroalkyl, aryl and heteroaryl are optionally substituted        with one to four substituents independently selected from R^(b),        provided that R⁵ is not —CH═CH—COOH;        R⁶ is selected from    -   (1) C₁₋₄alkyl,    -   (2) C₂alkenyl,    -   (3) C₂₋₄alkynyl,    -   (4) —OR^(d),    -   (5) halogen,    -   (6) —CN,    -   (7) —NR^(c)R^(d),    -   wherein alkyl, alkenyl, and alkynyl are optionally substituted        with one to four substituents independently selected from R^(a)        each R^(a) is independently selected from:    -   (1) —OR^(d),    -   (2) —NR^(c)S(O)_(m)R^(d),    -   (3) halogen,    -   (4) —S(O)_(m)R^(d),    -   (5) —S(O)_(m)NR^(c)R^(d),    -   (6) —NR^(c)R^(d),    -   (7) —C(O)R^(d),    -   (8) —CO₂R^(d),    -   (9) —CN,    -   (10) —C(O)NR^(c)R^(d),    -   (11) —NR^(c)C(O)R^(d),    -   (12) —NR^(c)C(O)OR^(d),    -   (13) —NR^(c)C(O)NR^(c)R^(d),    -   (14) —CF₃,    -   (15) —OCF₃, and    -   (16) cycloheteroalkyl;        each R^(b) is independently selected from:    -   (1) R^(a),    -   (2) C₁₋₁₀alkyl,    -   (3) oxo,    -   (4) aryl,    -   (5) arylC₁₋₄alkyl,    -   (6) heteroaryl, and    -   (7) heteroarylC₁₋₄alkyl;        R^(c) and R^(d) are independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl,    -   (3) C₂₋₁₀ alkenyl,    -   (4) cycloalkyl,    -   (5) cycloalkyl-C₁₋₁₀alkyl;    -   (6) cycloheteroalkyl,    -   (7) cycloheteroalkyl-C₁₋₁₀ alkyl;    -   (8) aryl,    -   (9) heteroaryl,    -   (10) aryl-C₁₋₁₀ alkyl, and    -   (11) heteroaryl-C₁₋₁₀alkyl, or        R^(c) and R^(d) together with the atom(s) to which they are        attached form a heterocyclic ring of 4 to 7 members containing        0-2 additional heteroatoms independently selected from oxygen,        sulfur and N—R^(g), each R^(c) and R^(d) may be unsubstituted or        substituted with one to three substituents selected from R^(h);        each R^(g) is independently selected from    -   (1) C₁₋₁₀alkyl, and    -   (2) —C(O)R^(c);        each R^(h) is independently selected from:    -   (1) halogen,    -   (2) C₁₋₁₀alkyl,    -   (3) —O-C₁₋₄alkyl,    -   (4) —S(O)_(m)-C₁₋₄ alkyl,    -   (5) —CN,    -   (6) —CF₃, and    -   (7) —OCF₃; and        m is selected from 0, 1 and 2.

In one embodiment of the present invention, when R¹ is unsubstitutedphenyl, R² is unsubstituted benzyl, R³ is unsubstituted methyl, and R⁴is hydrogen, then R⁵ is neither unsubstituted methyl nor unsubstitutedphenyl; and

when R¹ is unsubstituted benzyl, R² is unsubstituted phenyl, R³ isunsubstituted methyl, and R⁴ is hydrogen, then R⁵ is neitherunsubstituted methyl nor unsubstituted phenyl; and

when R¹ is unsubstituted phenyl, R² is 4-methoxybenzyl, R³ is methyl, R⁴is hydrogen, then R⁵ is not 3, 4, 5,-trimethoxyphenyl; and

when R¹ is 4-methoxybenzyl, R² is unsubstituted phenyl, R³ is methyl, R⁴is hydrogen, then R⁵ is not 3,4,5,-trimethoxyphenyl.

In another embodiment of the present invention, when R¹ is unsubstitutedphenyl, R² is unsubstituted benzyl, R³ is unsubstituted methyl, and R⁴is hydrogen, then R⁵ is not unsubstituted methyl, and

-   -   when R¹ is unsubstituted benzyl, R² is unsubstituted phenyl, R³        is unsubstituted methyl, and R⁴ is hydrogen, then R⁵ is not        unsubstituted methyl.

In one embodiment of the present invention, R¹ is selected from: aryl,aryl-C₁₋₄alkyl, heteroaryl, heteroaryl-C₁₋₄alkyl; wherein each alkyl isoptionally substituted with one to three substituents independentlyselected from R^(a), and each aryl and heteroaryl is optionallysubstituted with one to three substitutents independently selected fromR^(b).

In one class of this embodiment, R¹ is selected from:

phenyl, phenyl-C₁₋₄alkyl, pyridyl, and pyridyl-C₁₋₄allyl; wherein eachalkyl is optionally substituted with one or two R^(a) substituents andeach phenyl or pyridyl is independently with one to three R^(b)substituents.

In a subclass of this class of the present invention, R¹ is selectedfrom:

phenyl, phenyl-C₁₋₄alkyl, pyridyl, and pyridyl-C₁₋₄alkyl;

wherein each phenyl and pyridyl is optionally substituted with one ortwo substituents selected from halogen, methyl, trifluoromethyl, cyanoand methoxy, and each pyridyl is optionally present as the N-oxide.

In yet another subclass of this class of the present invention, R¹ isselected from:

phenyl, phenyl-C₁₋₄alkyl, pyridyl, and pyridyl-C₁₋₄alkyl;

wherein each phenyl and pyridyl is optionally substituted with one ortwo substituents selected from halogen, cyano and methoxy, and eachpyridyl is optionally present as the N-oxide.

In one particular subclass of compounds of the present invention, R¹ isselected from: phenyl, phenyl-C₁₋₄alkyl, pyridyl, and pyridyl-C₁₋₄alkyl;

wherein each phenyl is optionally substituted with one or twosubstituents selected from halogen, and methoxy, and each pyridyl isoptionally present as the N-oxide.

In still another subclass, R¹ is phenyl, unsubstituted or substitutedwith a halogen or cyano substituent.

In another embodiment of the present invention, R² is selected from:

C₁₋₁₀alkyl, C₃₋₁₀cycloalkyl-C₁₋₄alkyl, cycloheteroalkyl,cycloheteroalkyl-C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl, andheteroaryl-C₁₋₄alkyl; wherein each alkyl is optionally substituted withone to three substituents independently selected from R^(a), and eachcycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionallysubstituted with one to three substituents independently selected fromR^(b).

In one class of this embodiment of the present invention, R² is selectedfrom:

C₁₋₆-alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl, and heteroaryl-C₁₋₄alkyl;wherein each alkyl is optionally substituted with one R^(a) substituent,and each aryl and heteroaryl is optionally substituted with one to threesubstituents independently selected from R^(b).

In a subclass of this class of the present invention, aryl is phenyl andheteroaryl is pyridyl in R².

In another subclass of this class of the present invention, R² isselected from:

isopropyl, isobutyl, n-propyl, n-butyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl,phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and pyridylmethyl; whereineach cycloalkyl, aryl and heteroaryl is optionally substituted with oneor two R^(b) substituents selected from halogen, trifluoromethyl, cyano,methoxycarbonyl, and methoxy.

In yet another subclass, R² is benzyl, unsubstituted or substituted withhalogen, cyano, trifluoromethyl or methoxy. In still another subclass,R² is 4-chlorobenzyl.

In another embodiment of the present invention, R³ is selected from:

hydrogen, and C₁₋₄alkyl; wherein alkyl is optionally substituted withone or two substituents selected from R^(a).

In one class of this embodiment of the present invention, R³ is selectedfrom: hydrogen, methyl, ethyl, and isopropyl.

In one subclass of this class of the present invention, R³ is selectedfrom hydrogen, methyl and ethyl.

In another subclass of this class of the present invention, R³ ismethyl.

In another embodiment of the present invention, R⁴ is selected from:

hydrogen, and C₁₋₄alkyl; wherein alkyl is optionally substituted withone or two substituents selected from R^(a).

In one class of this embodiment of the present invention, R⁴ is selectedfrom:

hydrogen, and methyl.

In one subclass of this class, R⁴ is hydrogen.

In another embodiment of the present invention, R⁵ is selected from:

C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,cycloheteroalkyl-C₁₋₁₀alkyl, aryl-C₁₋₁₀alkyl, diaryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, heteroaryl-C₁₋₁₀alkyl, —OR^(d), S(O)_(m)R^(d), and—NR^(c)R^(d); wherein each alkyl or alkenyl is optionally substitutedwith one or two substituents independently selected from R^(a), and eachcycloalkyl, cycloheteroalkyl, aryl and heteroaryl is each optionallysubstituted with on to three substituents independently selected fromR^(b), provided that R⁵ is not —CH═CH—COOH.

In one class of this embodiment of the present invention, R⁵ is selectedfrom:

C₁₋₈alkyl, C₂₋₈alkenyl, cycloheteroalkyl-C₁₋₈alkyl, aryl-C₁₋₈alkyl,diaryl-C₁₋₈alkyl, aryl-C₂₋₈alkenyl, heteroaryl-C₁₋₈alkyl, —OR^(d), and—NR^(c)R^(d),

wherein each alkyl or alkenyl is optionally substituted with one or twosubstituents independently selected from R^(a), and each cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is each optionally substitutedwith on to three substituents independently selected from R^(b),provided that R⁵ is not —CH═CH—COOH.

In one subclass of this embodiment of the present invention, R⁵ isselected from:

C₁₋₈alkyl, C₂₋₈alkenyl, cycloheteroalkyl-C₁₋₈alkyl, aryl-C₁₋₈alkyl,diaryl-C₁₋₄alkyl, aryl-C₂₋₈alkenyl, heteroaryl-C₁₋₈alkyl, —OR^(d),and-NR^(c)R^(d); wherein: each alkyl or alkenyl is optionallysubstituted with one or two substituents independently selected fromR^(a), and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl iseach optionally substituted with one to three substituents independentlyselected from R^(b) and wherein aryl is selected from phenyl andnaphthyl; and heteroaryl is selected from pyridyl, pyrimidinyl,pyridazinyl, pyrazolyl, triazolyl, benzothiazolyl, benzoxazolinyl,isoxazolyl, indolyl and thiazolyl.

In a subclass of this class of the present invention, R⁵ is selectedfrom:

isopropyl, isobutyl, t-butyl, 1-ethyl-butyl, pentyl, benzyl,α-hydroxy-benzyl, α-aminobenzyl, α-dimethylamino-benzyl,α-methoxy-benzyl, α-hydroxy-diphenyl-methyl, 3-(aminosulfonyl)-propyl,5-(t-butyloxycarbonylamino)-pentyl, anilino, anilino-methyl, t-butoxy,phenoxy, benzyloxy, 1-naphthyl-methyl, phenyl-ethyl, 3-phenyl-propyl,3,3-diphenyl-propyl, 2-phenyl-ethylene, 1-phenyl-propyl, methoxymethyl,3-benzoyl-propyl, 7-benzoyl-heptyl, 2-t-butoxy-ethyl, phenoxy-methyl,1-phenoxy)-ethyl, 2-phenoxy)isopropyl, 2-(pyridyloxy)isopropyl,2-(pyrimidinyloxy)-isopropyl, 2-(pyridazinyloxy)-isopropyl,cyclopropyl-methyl, cyclopentyl-methyl, 2-(cyclohexyloxy)-isopropyl,(1-indanone)-3-methyl, (2-thiazolyl)-S-methyl,(2-benzothiazolyl)-S-methyl, (2-benzoxazolyl)-S-methyl,benztriazolyl-methyl, 2-benzothiazolyl)-ethyl, isoxazolyl-methyl,thiazolyl-methyl, triazolyl-methyl, 2-(triazolyl)-ethyl,pyrazolyl-methyl, 2-pyrazolyl)-ethyl, and (3-(1-oxo-isoindolyl))-methyl;

wherein each alkyl is optionally substituted with one or twosubstituents independently selected from R^(a), and each cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is each optionally substitutedwith on to three substituents independently selected from R^(b).

In yet another subclass of this class of the invention, R⁵ is selectedfrom:

C₁₋₈alkyl substituted with —OR^(d) or NR^(c)R^(d); C₂₋₈ alkenylsubstituted with OR^(d) or NR^(c)R^(d); and phenyl-C₁₋₈ alkyl whereinphenyl is substituted with one to three R^(b) substitutents.

In yet another subclass, R⁵ is selected from:

wherein the phenyl group may be substituted with one to three R^(b)substituents.

In one subclass of the present invention, R⁵ is

In another embodiment of the present invention, R⁶ is selected from:methyl, hydroxyl, halogen, —CN, and —NH₂; wherein methyl is optionallysubstituted with one to three R^(a) substituents.

In one class of this embodiment, R⁶ is selected from: methyl, hydroxyl,halogen, and —CN.

In one embodiment of the present invention, each R^(a) is independentlyselected from: —OR^(d), —NHS(O)_(m)R^(d), halogen, —S(O)_(m)R^(d),—S(O)_(m)NHR^(d), —NR^(c)R^(d), —C(O)R^(d), —CO₂R^(d), —CN,—C(O)NHR^(d), —NHC(O)R^(d), —NHC(O)OR^(d), —NHC(O)NHR^(d), —CF₃, —OCF₃,and cycloheteroalkyl.

In one class of this embodiment of the present invention, each R^(a) isindependently selected from: —OR^(d), —NHS(O)₂R^(d), halogen, —SR^(d),—SO₂R^(d), —S(O)₂NH₂, —NHR^(d), —N(CH₂CH₃)R^(d), —C(O)R^(d), —CO₂H, —CN,—C(O)NHR^(d), —NHC(O)R^(d), —NHC(O)OR^(d), —NHC(O)NHR^(d), —CF₃, —OCF₃,and cycloheteroalkyl.

In one subclass of this class, each R^(a) is independently selectedfrom: —OR^(d), halogen, —CN, —CF₃, and —OCF₃.

In one embodiment of the present invention, each R^(b) is independentlyselected from —OR^(d), —NHS(O)_(m)R^(d), halogen, —S(O)_(m)R^(d),—S(O)_(m)NHR^(d), —NHR^(d), —C(O)R^(d), —CO₂R^(d), —CN,—C(O)NR^(c)R^(d), —NHC(O)R^(d), —NHC(O)OR^(d), —NHC(O)NR^(c)R^(d), C₃,—OCF₃, cycloheteroalkyl, C₁₋₁₀alkyl, oxo, aryl, arylC₁₋₄alkyl,heteroaryl, and heteroarylC₁₋₄alkyl.

In one class of this embodiment of the present invention, each R^(b) isindependently selected from: —OR^(d), halogen, —CN, —CF₃, —OCF₃,—(O)₂R^(d), cycloheteroalkyl, C₁₋₄alkyl, oxo, phenyl, benzyl, andheteroaryl.

In one subclass of this class, each R^(b) is independently selected frommethoxy, halogen, —CN, —CF₃, —OCF₃, —S(O)₂R^(d), C₁₋₄alkyl, and oxo.

In another subclass of this class, each R^(b) is independently selectedfrom: halogen, —CN, —CF₃, —OCF₃, and methyl.

In still another subclass, each R^(b) is independently selected fromhalogen and cyano.

In one embodiment of the present invention, each R^(c) is independentlyselected from: hydrogen, and C₁₋₄alkyl; and each R^(d) is independentlyselected from: hydrogen, C₁₋₄alkyl, C₂₋₆ alkenyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl, cycloheteroalkyl, cycloheteroalkyl-1-4 alkyl,phenyl, heteroaryl, phenyl-C₁₋₄alkyl, and heteroaryl-C₁₋₄alkyl; or

R^(c) and R^(d) together with the atom(s) to which they are attachedform a heterocyclic ring of 4 to 7 members containing 0-2 additionalheteroatoms independently selected from oxygen, sulfur and N—R^(g), eachR^(c) and R^(d) may be unsubstituted or substituted with one to threesubstituents selected from R^(h).

In one class of this embodiment of the present invention, each R^(c) isindependently selected from: hydrogen, and C₁₋₄alkyl; and

each R^(d) is independently selected from hydrogen, C₁₋₅alkyl,—CH₂CH═CH₂, cyclohexyl, cyclopentyl, cyclopropyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, pyrrolidinyl, phenyl, thiazolyl,pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, benzoxazolyl,triazolyl, benzyl, and pyridyl-methyl-, or

R^(c) and R^(d) together with the atom(s) to which they are attachedform a piperidinyl ring,

each R^(c) and R^(d) may be unsubstituted or substituted with one tothree substituents selected from R^(h).

In one subclass, R^(c) is selected from hydrogen and methyl.

In another subclass, R^(d) is selected from phenyl and heteroaryl,unsubstituted or substituted with one to three R^(h) substituents.

In yet another subclass, R^(d) is selected from phenyl, pyridinyl,pyrimidinyl and pyridazinyl, unsubstituted or substituted with one tothree R^(h) substituents.

In still another subclass, R^(d) is selected from: phenyl,3-cyanophenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl,3,4,5-trifluorophenyl-3-chlorophenyl, 4-chlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-chlorophenyl, 3-fluoro-5-chlorophenyl,4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 5-trifluoromethyl-2-pyridyl,4-trifluoromethyl-2-pyridyl, 6-chloro-2-pyridyl, 5-chloro-2-pyridyl,4,6-dimethyl-2-pyridyl, 6-methyl-2-pyridyl, 5-methylsulfonyl-2-pyridyl,2-pyrimidinyl, 5-chloro-2-pyrimidinyl, 4-trifluoromehtyl-2-pyrimidinyl,4-pyrimidinyl, 6-trifluoromethyl-4-pyrimidinyl, and 3-pyridazinyl.

In one embodiment of the present invention, each R^(g) is independentlyselected from C₁₋₄alkyl, and —C(O)C₁₋₄alkyl.

In one class of this embodiment, each R^(g) is methyl or methylcarbonyl.

In one subclass of this class, each R^(g) is methyl.

In one embodiment of the present invention, each R^(h) is independentlyselected from: halogen, C₁₋₄alkyl, —O-C₁₋₄alkyl, —S—(O)_(m)C₁₋₄alkyl,—CN, —CF₃, and —OCF₃.

In one class of this embodiment, each R^(h) is independently selectedfrom: halogen, methyl, methoxy, methylthio, methylsulfonyl, —CN, CF₃,and —OCF₃.

In one subclass, each R^(h) is independently selected from: halogen,methyl, methoxy, methylsulfonyl, —CN, —CF₃, and —OCF₃.

In one embodiment of the present invention, m is selected from zero andtwo.

In a class of this embodiment, m is two.

Particular novel compounds which may be employed in the methods, usesand compositions of the present invention, include:N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-4chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-3-cyanophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(R)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-3-[2-phenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-[2-(4-chlorophenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-methyl-3-[2-phenyl)ethyl)urea,1-{[3(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-[1-(4-chlorophenyl)ethyl)urea,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenylbutanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-1-ethyl-cyclobutanecarboxamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-1-phenyl-cyclobutanecarboxamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-[(S)-methyl]propyl}-2-phenyl-butanamide,and pharmaceutically acceptable salts thereof.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclicrings, each of which having from 3 to 10 carbon atoms. The term alsoincludes monocyclic rings fused to an aryl group in which the point ofattachment is on the non-aromatic portion. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.

“Aryl” means mono- or bicyclic aromatic rings containing only carbonatoms. The term also includes aryl group fused to a monocycliccycloalkyl or monocyclic cycloheteroalkyl group in which the point ofattachment is on the aromatic portion. Examples of aryl include phenyl,naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.

“Heteroaryl” means a mono- or bicyclic aromatic ring containing at leastone heteroatom selected from N, O and S, with each ring containing 5 to6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenylfuro(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, imidazothiazolyl,and the like. The heteroaryl ring may be substituted on one or morecarbon or nitrogen atoms

“Cycloheteroalkyl” means mono- or bicyclic or bridged saturated ringscontaining at least one heteroatom selected from N, S and O, each ofsaid ring having from 3 to 10 atoms in which the point of attachment maybe carbon or nitrogen. The term also includes monocyclic heterocyclefused to an aryl or heteroaryl group in which the point of attachment ison the non-aromatic portion. Examples of “cycloheteroalkyl” includepyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl,2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl,2-H-phthalazinyl, isoindolinyl,benzoxazepinyl,5,6-dihydroimidazo[2,1-b]thiazolyl,tetrahydrohydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl,dihydroindolyl, and the like. The term also includes partiallyunsaturated monocyclic rings that are not aromatic, such as 2- or4-pyridones attached through the nitrogen orN-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). Theterm also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl,7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, andazabicyclo[2.2.1]heptanyl. The cycloheteroalkyl ring may be substitutedon the ring carbons and/or the ring nitrogens.

“Halogen” includes fluorine, chlorine, bromine and iodine.

When any variable (e.g., R¹, R^(d), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or ethyl acetate or a mixturethereof. The pair of enantiomers thus obtained may be separated intoindividual stereoisomers by conventional means, for example by the useof an optically active amine as a resolving agent or on a chiral HPLCcolumn.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum ammonium, calcium, copper, ferric,ferrous, lithium magnesium, manganic salts, manganous, potassium,sodium, zinc, and the like. Particularly preferred are the ammonium,calcium, magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. The term “pharmaceutically acceptable salt”further includes all acceptable salts such as acetate, lactobionate,benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate,bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide,bromide, methylnitrate, calcium edetate, methylsulfate, camsylate,mucate, carbonate, napsylate, chloride, nitrate, clavulanate,N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate,edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate,esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate,polygalacturonate, gluconate, salicylate, glutamate, stearate,glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine,succinate, hydrobromide, tannate, hydrochloride, tatrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and the like which can be usedas a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-rugformulations.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Compounds of the present invention are modulators of the CB1 receptor.In particular, the compounds of structural formula I are antagonists orinverse agonists of the CB1 receptor.

An “agonist” is a compound (hormone, neurotransmitter or syntheticcompound) which binds to a receptor, inducing a conformational change inthe receptor which, in turn, produces a response such as contraction,relaxation, secretion, change in enzyme activity, etc. similar to thatelicited by the physiologically relevant agonist ligand(s) for thatreceptor. An “antagonist” is a compound which attenuates the effect ofan agonist. An “inverse agonist” is a compound which acts on a receptorbut produces the opposite effect produced by the agonist of theparticular receptor.

Compounds of this invention are modulators of the CB1 receptor and assuch are useful as centrally acting drugs in the treatment of psychosis,memory deficits, cognitive disorders, migraine, neuropathy,neuro-inflammatory disorders including multiple sclerosis andGuillain-Barre syndrome and the inflammatory sequelae of viralencephalitis, cerebral vascular accidents, and head trauma, anxietydisorders, stress, epilepsy, Parkinson's disease, movement disorders,and schizophrenia. The compounds are also useful for the treatment ofsubstance abuse disorders, particularly to opiates, alcohol, marijuana,and nicotine. The compounds are also useful for the treatment of obesityor eating disorders associated with excessive food intake andcomplications associated therewith. The compounds are also useful forthe treatment of constipation and chronic intestinal pseudo-obstruction.The compounds are also useful for the treatment of cirrhosis of theliver. The compounds are also useful for the treatment of asthma.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The utilities of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature. The following are examples of such animal diseasemodels: a) suppression of food intake and resultant weight loss in rats(Life Sciences 1998, 63, 113-117); b) reduction of sweet food intake inmarmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucroseand ethanol intake in mice (Psychopharm. 1997, 132, 104-106); d)increased motor activity and place conditioning in rats (Psychopharm.1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e) spontaneouslocomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f)reduction in opiate self-administration in mice (Sci. 1999, 283,401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs asmodels for the various phases of asthma (for example, see W. M. Abrahamet al., “α₄-Integrins mediate antigen-induced late bronchial responsesand prolonged airway hyperresponsiveness in sheep.” J. Clin. Invest. 93,776 (1993) and A. A. Y. Milne and P. P. Piper, “Role of VLA-4 integrinin leucocyte recruitment and bronchial hyperresponsiveness in thegunea-pig.” Eur. J. Pharmacol., 282, 243 (1995)); h) mediation of thevasodilated state in advanced liver cirrhosis induced by carbontetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i)amitriptyline-induced constipation in cynomolgus monkeys is beneficialfor the evaluation of laxatives (Biol. Pharm. Bulletin (Japan), 2000,23(5), 657-9); j) neuropathology of paediatric chronic intestinalpseudo-obstruction and animal models related to the neuropathology ofpaediatric chronic intestinal pseudo-obstruction (Journal of PathologyEngland), 2001, 194 (3), 277-88).

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range lie within the range of from about 0.001 mg to about 100 mgper kg body weight of a mammal, preferably 0.01 mg to about 50 mg perkg, and most preferably 0.1 to 10 mg per kg, in single or divided doses.On the other hand, it may be necessary to use dosages outside theselimits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 25 mg(preferably from 0.01 mg to about 1 mg) of a compound of Formula I perkg of body weight per day and for preventive use from about 0.1 mg toabout 100 mg (preferably from about 1 mg to about 100 mg and morepreferably from about 1 mg to about 10 mg) of a compound of Formula Iper kg of body weight per day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1000 mg of a compound ofFormula I per day, preferably from about 0.1 mg to about 10 mg per day.For oral administration, the compositions are preferably provided in theform of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05,0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. In particular,the term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery systems for inhalation are metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of Formula I in suitable propellants, such asfluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol,which may be formulated as a dry powder of a compound of Formula I withor without additional excipients.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to 5% by weight of the active compoundin admixture with a pharmaceutically acceptable vehicle. Transdermalskin patches useful for administering the compounds of the presentinvention include those well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules(including timed release and sustained release formulations), pills,cachets, powders, granules or tablets each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion or a water-in-oil liquid emulsion, incluidngelixirs, tinctures, solutions, suspensions, syrups and emulsions. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine, the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet containsfrom 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5,6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and1,000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated, and each cachet or capsulecontains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200,225, 500, 750 and 1,000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated.

Additional suitable means of administration of the compounds of thepresent invention include injection, intravenous bolus or infusion,intraperitoneal, subcutaneous, intramuscular and topical, with orwithout occlusion.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I: Injectable Suspension (I.M.) mg/mLCompound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol9.0 Benzalkonium chloride 1.0 Water for injection to a total volume of 1mL Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5Magnesium Stearate 1.5 600 Tablet mg/tablet Compound of Formula I 25Microcrystalline Cellulose 415 Povidone 14.0 Pregelatinized Starch 43.5Magnesium Stearate 2.5 500 Aerosol Per canister Compound of Formula I 24mg Lecithin, NF Liq. Conc. 1.2 mg Trichlorofluoromethane, NF 4.025 gDichlorodifluoromethane, NF 12.15 g

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I. Examples of other activeingredients that may be combined with a compound of Formula I include,but are not limited to: antipsychotic agents, cognition enhancingagents, anti-migraine agents, anti-asthmatic agents, antiinflammatoryagents, axiolytics, anti-Parkinson's agents, anti-epileptics, anorecticagents, and serotonin reuptake inhibitors, which may be administeredseparately or in the same pharmaceutical compositions.

The present invention also provides a method for the treatment orprevention of a CB1 receptor modulator mediated disease, which methodcomprises administration to a patient in need of such treatment or atrisk of developing a CB1 receptor modulator mediated disease of anamount of a CB1 receptor modulator and an amount of one or more activeingredients, such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CB1 receptor modulator and oneor more active ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and one or more activeingredients for the manufacture of a medicament for the treatment orprevention of a CB1 receptor modulator mediated disease. In a further oralternative aspect of the present invention, there is therefore provideda product comprising a CB1 receptor modulator and one or more activeingredients as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of CB1 receptor modulatormediated disease. Such a combined preparation may be, for example, inthe form of a twin pack.

It will be appreciated that for the treatment or prevention of eatingdisorders, including obesity, bulimia nervosa and compulsive eatingdisorders, a compound of the present invention may be used inconjunction with other anorectic agents.

The present invention also provides a method for the treatment orprevention of eating disorders, which method comprises administration toa patient in need of such treatment an amount of a compound of thepresent invention and an amount of an anorectic agent, such thattogether they give effective relief.

Suitable anoretic agents for use in combination with a compound of thepresent invention include, but are not limited to, aminorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

A particularly suitable class of anorectic agent are the halogenatedamphetamine derivatives, including chlorphentermine, cloforex,clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;and pharmaceutically acceptable salts thereof.

Particularly preferred halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith a selective serotonin reuptake inhibitor (SSRI).

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an SSRI, such that together they giveeffective relief.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment or prevention, an amount of a compoundof the present invention and an amount of growth hormone secretagoguessuch as those disclosed and specifically described in U.S. Pat. No.5,536,716; melanocortin agonists such as Melanotan II or those describedin WO 99/64002, WO 00/74679, WO 01/70708, WO 01/70337, WO 01/91752 andWO 02/15909; β-3 agonists such as those disclosed and specificallydescribed in patent publications WO94/18161, WO95/29159, WO97/46556,WO98/04526 and WO98/32753; 5HT-2 agonists; orexin antagonists; melaninconcentrating hormone antagonists; galanin antagonists; CCK agonists;GLP-1 agonists; corticotropin-releasing hormone agonists; NPY-5antagonists; Y1 antagonists, histamine receptor-3 (H3) modulators,melanin concentrating hormone-1 receptor (MCH1R) antagonists, melaninconcentrating hormone-2 receptor (MCH2R) agonists and antagonists and/orphosphodiesterase-3B (PDE3B) inhibitors, such that together they giveeffective relief.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith an opioid antagonist.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an opioid antagonist, such that together theygive effective relief.

Suitable opioid antagonists of use in combination with a compound of thepresent invention include: naloxone, naltrexone, and nalmefene, andpharmaceutically acceptable salts thereof.

It will be appreciated that for the treatment or prevention of obesity,the compounds of the present invention may also be used in combinationwith inhibitors of the enzyme 11

-HSD1. Generally, glucocorticoid concentrations are modulated bytissue-specific 11β-hydroxysteroid dehydrogenase enzymes. The11β-hydroxysteroid dehydrogenase type 1 enzyme (11

-HSD1) is a low affinity enzyme that generally uses NADP+ as a cofactorrather than NAD+ (Agarwal et al., 1989). In vitro studies have shownthat 11

-HSD1 is capable of acting as both a reductase and a dehydrogenase.However, 11

-HSD1 in vivo generally acts as a reductase, converting11-ketoglucocorticoids, such as cortisone, to 11

-hydroxyglucocorticoids such as cortisol.

Excessive levels of cortisol have been associated with obesity, perhapsdue to increased hepatic gluconeogenesis. Thus, the administration of aneffective amount of an 11

-HSD1 inhibitor in combination with a CB1 antagonist of the presentinvention may be useful in the treatment or control of obesity.Particular inhibitors of 11

-HSD1 useful in combination with the compounds of the present inventioninclude: 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,3-(1-adamantyl)-5-3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole,and3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene.

“Obesity” is a condition in which there is an excess of body fat. Theoperational definition of obesity is based on the Body Mass Index (BMI),which is calculated as body weight per height in meters squared (kg/m²).“Obesity” refers to a condition whereby an otherwise healthy subject hasa Body Mass Index (BMI) greater than or equal to 30 kg/m², or acondition whereby a subject with at least one co-morbidity has a BMIgreater than or equal to 27 kg/m². An “obese subject” is an otherwisehealthy subject with a Body Mass Index (BMI) greater than or equal to 30kg/m² or a subject with at least one co-morbidity with a BMI greaterthan or equal to 27 kg/m². A “subject at risk for obesity” is anotherwise healthy subject with a BMI of 25 kg/m² to less than 30 kg/m²or a subject with at least one co-morbidity with a BMI of 25 kg/m² toless than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asian countries, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus—type 2,impaired glucose tolerance, impaired fasting glucose, insulin resistancesyndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronaryartery disease, myocardial infarction, angina pectoris, sleep apneasyndrome, Pickwickian syndrome, fatty liver, cerebral infarction,cerebral thrombosis, transient ischemic attack, orthopedic disorders,arthritis deformans, lumbodynia, emmeniopathy, and infertility. Inparticular, co-morbidities include: hypertension, hyperlipidemia,dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea,diabetes mellitus, and other obesity-related conditions.

“Treatment” (of obesity and obesity-related disorders) refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

“Prevention” (of obesity and obesity-related disorders) refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer. The compounds of the present inventionare also useful for reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type I diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as TypeII diabetes. Type I diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type II diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type II diabetics are also obese. The compounds of thepresent invention are useful for treating both Type I and Type IIdiabetes. The compounds are especially effective for treating Type IIdiabetes. The compounds of the present invention are also useful fortreating and/or preventing gestational diabetes mellitus.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents.

Suitable classes of anti-depressant agents include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists andatypical anti-depressants.

Suitable norepinephrine reuptake inhibitors include tertiary aminetricyclics and secondary amine tricyclics. Suitable examples of tertiaryamine tricyclics include: amitriptyline, clomipramine, doxepin,imipramine and trimipramine, and pharmaceutically acceptable saltsthereof. Suitable examples of secondary amine tricyclics include:amoxapine, desipramine, maprotiline, nortriptyline and protriptyline,and pharmaceutically acceptable salts thereof.

Suitable selective serotonin reuptake inhibitors include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable monoamine oxidase inhibitors include: isocarboxazid,phenelzine, tranylcypromine and selegiline, and pharmaceuticallyacceptable salts thereof.

Suitable reversible inhibitors of monoamine oxidase include:moclobemide, and pharmaceutically acceptable salts thereof.

Suitable serotonin and noradrenaline reuptake inhibitors of use in thepresent invention include: venlafaxine, and pharmaceutically acceptablesalts thereof.

Suitable CRF antagonists include those compounds described inInternational Patent Specification Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677.

Suitable neurokinin-1 receptor antagonists may be peptidal ornon-peptidal in nature, however, the use of a non-peptidal neurokinin-1receptor antagonist is preferred. In a preferred embodiment, theneurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1receptor antagonist. In addition, for convenience the use of an orallyactive neurokinin-1 receptor antagonist is preferred. To facilitatedosing, it is also preferred that the neurokinin-1 receptor antagonistis a long acting neurokinin-1 receptor antagonist. An especiallypreferred class of neurokinin-1 receptor antagonists of use in thepresent invention are those compounds which are orally active and longacting.

Neurokinin-1 receptor antagonists of use in the present invention arefully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930,5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833,5,637,699; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913,0590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International PatentPublication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688,92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677,92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170,93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064,93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461,94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843,94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639,94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735,94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886,95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382,95/18124, 95/18129, 95/19344, 95/20575,95/21819, 95/22525, 95/23798,95/26338,95/28418, 95/30674; 95/30687; 95/33744, 96/05181, 96/05193,96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197,96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385,96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362,97/18206, 97/19084, 97/19942, 97/21702, 97/49710, 98/24438-98/24441,98/24442-98/24445, 02/16343, and 02/16344; and in British PatentPublication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774,2 292 144, 2 293 168, 2 293 169, and 2 302 689.

Specific neurokinin-1 receptor antagonists of use in the presentinvention include:(±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-S)-phenyl-morpholine;2-S)-3,5-bis(trifluoromethyl)benzyloxy)4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;2(R>(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-S)-4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;2-(R)-1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazolyl)methyl-3-S)-(4-fluorophenyl)morpholine;(3S,5R,6S-3-[2-cyclopropoxy-5-(fluoromethoxy)phenyl]6-phenyl-1-oxa-7-aza-spiro[4.5]decane;(3R,5R,6S)-3-[2-cyclopropoxy-5-trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;2-(R)-(1-(S)-3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-S)-4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;2-R)-1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;2-S-(1-(R)-1-(R)(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3,2S)-4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;2-S)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-4-fluorophenyl)morpholine;or a pharmaceutically acceptable salt thereof.

Suitable atypical anti-depressants include: bupropion, lithium,nefazodone, trazodone and viloxazine, and pharmaceutically acceptablesalts thereof.

Suitable classes of anti-anxiety agents include benzodiazepines and5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partialagonists, and corticotropin releasing factor (CRF) antagonists.

Suitable benzodiazepines include: alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepam, halazepam, lorazepam oxazepam andprazepam, and pharmaceutically acceptable salts thereof.

Suitable 5-HT_(1A) receptor agonists or antagonists include, inparticular, the 5-HT_(1A) receptor partial agonists buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

Suitable corticotropin releasing factor (CRF) antagonists include thosepreviously discussed herein.

As used herein, the term “substance abuse disorders” includes substancedependence or abuse with or without physiological dependence. Thesubstances associated with these disorders are: alcohol, amphetamines(or amphetamine-like substances), caffeine, cannabis, cocaine,hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine(or phencyclidine-like compounds), sedative-hypnotics orbenzodiazepines, and other (or unknown) substances and combinations ofall of the above.

In particular, the term “substance abuse disorders” includes drugwithdrawal disorders such as alcohol withdrawal with or withoutperceptual disturbances; alcohol withdrawal delirium; amphetaminewithdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal;sedative, hypnotic or anxiolytic withdrawal with or without perceptualdisturbances; sedative, hypnotic or anxiolytic withdrawal delirium; andwithdrawal symptoms due to other substances. It will be appreciated thatreference to treatment of nicotine withdrawal includes the treatment ofsymptoms associated with smoking cessation.

Other “substance abuse disorders” include substance-induced anxietydisorder with onset during withdrawal; substance-induced mood disorderwith onset during withdrawal; and substance-induced sleep disorder withonset during withdrawal.

It will be appreciated that a combination of a conventionalantipsychotic drug with a CB1 receptor modulator may provide an enhancedeffect in the treatment of mania. Such a combination would be expectedto provide for a rapid onset of action to treat a manic episode therebyenabling prescription on an “as needed basis”. Furthermore, such acombination may enable a lower dose of the antispychotic agent to beused without compromising the efficacy of the antipsychotic agent,thereby minimizing the risk of adverse side-effects. A yet furtheradvantage of such a combination is that, due to the action of the CB1receptor modulator, adverse side-effects caused by the antipsychoticagent such as acute dystonias, dyskinesias, akathesia and tremor may bereduced or prevented.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an antipsychotic agentfor the manufacture of a medicament for the treatment or prevention ofmania.

The present invention also provides a method for the treatment orprevention of mania, which method comprises administration to a patientin need of such treatment or at risk of developing mania of an amount ofa CB1 receptor modulator and an amount of an antipsychotic agent, suchthat together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CB1 receptor modulator and anantipsychotic agent, together with at least one pharmaceuticallyacceptable carrier or excipient.

It will be appreciated that the CB1 receptor modulator and theantipsychotic agent may be present as a combined preparation forsimultaneous, separate or sequential use for the treatment or preventionof mania. Such combined preparations may be, for example, in the form ofa twin pack

In a further or alternative aspect of the present invention, there istherefore provided a product comprising a CB1 receptor modulator and anantipsychotic agent as a combined preparation for simultaneous, separateor sequential use in the treatment or prevention of mania.

It will be appreciated that when using a combination of the presentinvention, the CB1 receptor modulator and the antipsychotic agent may bein the same pharmaceutically acceptable carrier and thereforeadministered simultaneously. They may be in separate pharmaceuticalcarriers such as conventional oral dosage forms which are takensimultaneously. The term “combination” also refers to the case where thecompounds are provided in separate dosage forms and are administeredsequentially. Therefore, by way of example, the antipsychotic agent maybe administered as a tablet and then, within a reasonable period oftime, the CB1 receptor modulator may be administered either as an oraldosage form such as a tablet or a fast-dissolving oral dosage form. By a“fast dissolving oral formulation” is meant, an oral delivery form whichwhen placed on the tongue of a patient, dissolves within about 10seconds.

Included within the scope of the present invention is the use of CB1receptor modulators in combination with an antipsychotic agent in thetreatment or prevention of hypomania.

It will be appreciated that a combination of a conventionalantipsychotic drug with a CB1 receptor modulator may provide an enhancedeffect in the treatment of schizophrenic disorders. Such a combinationwould be expected to provide for a rapid onset of action to treatschizophrenic symptoms thereby enabling prescription on an “as neededbasis”. Furthermore, such a combination may enable a lower dose of theCNS agent to be used without compromising the efficacy of theantipsychotic agent, thereby minimizing the risk of adverseside-effects. A yet further advantage of such a combination is that, dueto the action of the CB1 receptor modulator, adverse side-effects causedby the antipsychotic agent such as acute dystonias, dyskinesias,akathesia and tremor may be reduced or prevented.

As used herein, the term “schizophrenic disorders” includes paranoid,disorganized, catatonic, undifferentiated and residual schizophrenia;schizophreniform disorder, schizoaffective disorder; delusionaldisorder; brief psychotic disorder, shared psychotic disorder;substance-induced psychotic disorder; and psychotic disorder nototherwise specified.

Other conditions commonly associated with schizophrenic disordersinclude self-injurious behavior (e.g. Lesch-Nyhan syndrome) and suicidalgestures.

Suitable antipsychotic agents of use in combination with a CB1 receptormodulator include the phenothiazine, thioxanthene, heterocyclicdibenzazepine, butyrophenone, diphenylbutylpiperidine and indoloneclasses of antipsychotic agent. Suitable examples of phenothiazinesinclude chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine. Suitable examples ofthioxanthenes include chlorprothixene and thiothixene. Suitable examplesof dibenzazepines include clozapine and olanzapine. An example of abutyrophenone is haloperidol. An example of a diphenylbutylpiperidine ispimozide. An example of an indolone is molindolone. Other antipsychoticagents include loxapine, sulpiride and risperidone. It will beappreciated that the antipsychotic agents when used in combination witha CB1 receptor modulator may be in the form of a pharmaceuticallyacceptable salt, for example, chlorpromazine hydrochloride, mesoridazinebesylate, thioridazine hydrochloride, acetophenazine maleate,fluphenazine hydrochloride, flurphenazine enathate, fluphenazinedecanoate, trifluoperazine hydrochloride, thiothixene hydrochloride,haloperidol decanoate, loxapine succinate and molindone hydrochloride.Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol,pimozide and risperidone are commonly used in a non-salt form.

Other classes of antipsychotic agent of use in combination with a CB1receptor modulator include dopamine receptor antagonists, especially D2,D3 and D4 dopamine receptor antagonists, and muscarinic m1 receptoragonists. An example of a D3 dopamine receptor antagonist is thecompound PNU-99194A. An example of a D4 dopamine receptor antagonist isPNU-101387. An example of a muscarinic m1 receptor agonist isxanomeline.

Another class of antipsychotic agent of use in combination with a CB1receptor modulator is the 5-HT_(2A) receptor antagonists, examples ofwhich include MDL100907 and fananserin. Also of use in combination witha CB1 receptor modulator are the serotonin dopamine antagonists (SDAs)which are believed to combine 5-HT_(2A) and dopamine receptor antagonistactivity, examples of which include olanzapine and ziperasidone.

It will be appreciated that a combination of a conventionalanti-asthmatic drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of asthma.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-asthmatic agentfor the manufacture of a medicament for the treatment or prevention ofasthma.

The present invention also provides a method for the treatment orprevention of asthma, which method comprises administration to a patientin need of such treatment an amount of a compound of the presentinvention and an amount of an anti-asthmatic agent, such that togetherthey give effective relief.

Suitable anti-asthmatic agents of use in combination with a compound ofthe present invention include, but are not limited to: (a) VLA-4antagonists such as natalizumab and the compounds described in U.S. Pat.No. 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966,WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b)steroids and corticosteroids such as beclomethasone, methylprednisolone,betamethasone, prednisone, dexamethasone, and hydrocortisone; (c)antihistamines (H1-histamine antagonists) such as bromopheniramine,chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine,antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine,desloratadine, cetirizine, fexofenadine, descarboethoxyloratadine, andthe like; (d) non-steroidal anti-asthmatics including β2-agonists (suchas terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,bitolterol, salmeterol, epinephrine, and pirbuterol), theophylline,cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists(such as zafirlukast, montelukast, pranlukast, iralukast, pobilukast,and SKB-106,203), and leukotriene biosynthesis inhibitors (such aszileuton and BAY-1005); (e) anti-cholinergic agents including muscarinicantagonists (such as ipratropium bromide and atropine); (f) antagonistsof the chemokine receptors, especially CCR-1, CCR-2, and CCR-3; (g)immunosuppressants such as cyclosporin, tacrolimus, rapamycin and otherFK-506 type immunosuppressants; (h) non-steroidal antiinflammatoryagents (NSAIDs) such as propionic acid derivatives (alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, andtioxaprofen), acetic acid derivatives (indomethacin, acemetacin,alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac,tolmetin, zidometacin, and zomepirac), fenamic acid derivatives(flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid andtolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal andflufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones(apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone,phenylbutazone); (i) cyclooxygenase-2 (COX-2) inhibitors such ascelecoxib; (j) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone, pioglitazone, englitazone, MCC-555, BRL-49653and the like); (k) preparations of interferon beta (interferon beta-1a,interferon beta-1b); (1) other compounds such as 5-aminosalicylic acidand prodrugs thereof, and pharmaceutically acceptable salts thereof.

It will be appreciated that a combination of a conventionalanti-constipation drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of constipation.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-constipationagent for the manufacture of a medicament for the treatment orprevention of constipation.

The present invention also provides a method for the treatment orprevention of constipation, which method comprises administration to apatient in need of such treatment an amount of a compound of the presentinvention and an amount of an anti-constipation agent, such thattogether they give effective relief.

It will be appreciated that a combination of a conventionalanti-constipation drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of chronic intestinalpseudo-obstruction.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-constipationagent for the manufacture of a medicament for the treatment orprevention of chronic intestinal pseudo-obstruction.

The present invention also provides a method for the treatment orprevention of chronic intestinal pseudo-obstruction, which methodcomprises administration to a patient in need of such treatment anamount of a compound of the present invention and an amount of ananti-constipation agent, such that together they give effective relief.

Suitable anti-constipation agents of use in combination with a compoundof the present invention include, but are not limited to, osmoticagents, laxatives and detergent laxatives (or wetting agents), bulkingagents, and stimulants; and pharmaceutically acceptable salts thereof.

A particularly suitable class of osmotic agents include, but are notlimited to sorbitol, lactulose, polyethylene glycol, magnesium,phosphate, and sulfate; and pharmaceutically acceptable salts thereof.

A particularly suitable class of laxatives and detergent laxatives,include, but are not limited to, magnesium, and docusate sodium; andpharmaceutically acceptable salts thereof.

A particularly suitable class of bulking agents include, but are notlimited to, psyllium, methylcellulose, and calcium polycarbophil; andpharmaceutically acceptable salts thereof.

A particularly suitable class of stimulants include, but are not limitedto, anthroquinones, and phenolphthalein; and pharmaceutically acceptablesalts thereof.

It will be appreciated that a combination of a conventionalanti-cirrhosis drug with a CB1 receptor modulator may provide anenhanced effect in the treatment of cirrhosis of the liver.

Thus, according to a further aspect of the present invention there isprovided the use of a CB1 receptor modulator and an anti-cirrhosis agentfor the manufacture of a medicament for the treatment or prevention ofcirrhosis of the liver.

The present invention also provides a method for the treatment orprevention of cirrhosis of the liver, which method comprisesadministration to a patient in need of such treatment an amount of acompound of the present invention and an anti-cirrhosis agent, such thattogether they give effective relief.

Suitable anti-cirrhosis agents of use in combination with a compound ofthe present invention include, but are not limited to, corticosteroids,penicillamine, colchicine, interferon-γ, 2-oxoglutarate analogs,prostaglandin analogs, and other anti-inflammatory drugs andantimetabolites such as azathioprine, methotrexate, leflunamide,indomethacin, naproxen, and 6-mercaptopurine; and pharmaceuticallyacceptable salts thereof.

The method of treatment of this invention comprises a method ofmodulating the CB1 receptor and treating CB1 receptor mediated diseasesby administering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of this invention thatselectively antagonizes the CB1 receptor in preference to the other CBor G-protein coupled receptors.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel mehtods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a β-3 agonistthe weight ratio of the compound of the Formula I to the β-3 agonistwill generally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the Formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Abbreviations used in the following Schemes and Examples: aq.: aqueous;API-ES: atmospheric pressure ionization-electrospray (mass spectrumterm); DEAD: diethyl azodicarboxylate; DMAP: 4-dimethylaminopyridine;DMF: dimethylformamide; DMSO: dimethylsulfoxide; EDC:1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride; EPA:ethylene polyacrylamide (a plastic); EtOAc: ethyl acetate; g: gram; h:hours' HOBt: 1-hydroxybenzotriazole; HPLC: high pressure liquidchromatography; HPLC/MS: high pressure liquid chromatography/massspectrum; in vacuo: rotoevaporation; LC: Liquid chromatography; LC/MS,LC-MS: liquid chromatography-mass spectrum; LDA: lithium diisopropylamide; M: molar, Me: methyl; MeOH: methanol; MHz: megahertz; min:minute; mL: milliliter; mmol: millimole; MS or ms: mass spectrum; N:normal; NaHMDS: sodium hexamethyldisilazide; NMR: nuclear magneticresonance; PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; R_(t): retention time; rt or RT: room temperature;TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layerchromatography.

Compounds of the present invention may be prepared by proceduresillustrated in the accompanying scheme.

In Scheme 1, an appropriately substituted amine A is reacted with acarboxylic acid B under standard amide bond forming conditions to affordthe arylamide C.

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of reducing the invention to practice. Those skilledin the art may find other methods of practicing the invention which arereadily apparent to them. However, those methods are also deemed to bewithin the scope of this invention.

General Procedures.

The LC/MS analyses were preformed using a MICROMASS ZMD massspectrometer coupled to an AGILENT 1100 Series HPLC utilizing a YMCODS-A 4.6×50 mm column eluting at 2.5 mL/min with a solvent gradient of10 to 95% B over 4.5 min, followed by 0.5 min at 95% B: solvent A=0.06%TFA in water, solvent B=0.05% TFA in acetonitrile. ¹H-NMR spectra wereobtained on a 500 MHz VARIAN Spectrometer in CDCl₃ or CD₃OD as indicatedand chemical shifts are reported as 8 using the solvent peak asreference and coupling constants are reported in hertz (Hz).

REFERENCE EXAMPLE 1

2-(2-Fluorophenyloxy)-2-methylpropionic acid

To a solution of 2-fluorophenol (2.0 g, 18 mmol) and1,1,1-trichloro-2-methyl-2-propanol (7.9 g, 45 mmol) in acetone (100 mL)was added sodium hydroxide (7.1 g, 0.18 mol), and an ice-water bath wasperiodically applied to maintain a gentle reflux. After the refluxsubsided, the reaction was stirred for one additional hour. The volatilematerials were removed on a rotary evaporator, and the residuepartitioned between ether (100 mL), hexane (100 mL) and water (200 mL).The aqueous layer was separated and acidified with concentratedhydrochloric acid (pH=2), and extracted with ether (3×100 mL). Thecombined extracts were dried over anhydrous magnesium sulfate, filtered,and concentrated to dryness to give the title compound, which was usedwithout further purification. ¹H NMR (500 MHz, CD₃OD): δ 7.15-7.05 (m,4H), 1.56 (s, 6H). LC-MS: m/e 199 (M+1)⁺ (2.3 min).

The acids of Reference Examples 2-12 were prepared following theprocedures described for Reference Example 1 substituting 2-fluorophenolwith appropriately substituted phenols.

REFERENCE EXAMPLE 2

2-(3-Fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.26 (ddd, 1H), 6.77-6.70 (m, 2H), 6.64 (dt,1H), 1.59 (s, 6H). LC-MS: m/e 199 (M+1)⁺, (2.4 min).

REFERENCE EXAMPLE 3

2-(4-Fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.02-6.92 (m, 4H), 1.54 (s, 6H).

REFERENCE EXAMPLE 4

2-(3 Chlorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.23 (t, 1H), 7.00 (dd, 1H), 6.93 (t, 1H),6.84 (dd, 1H), 1.59 (s, 6H). LC-MS: m/e 215 (M+1)⁺, (2.7 min).

REFERENCE EXAMPLE 5

2-(3-Cyanophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.44 (dd, 1H), 7.36 (d, 1H), 7.22 (m, 2H),1.62 (s, 6H).

REFERENCE EXAMPLE 6

2-(3,4-Difluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.16 (q, 1H), 6.86 (dddd, 1H), 6.72 (m, 1H),1.57 (s, 6H). LC-MS: m/e 217 (M+1)⁺, (2.5 min).

REFERENCE EXAMPLE 7

2-3,5-Difluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 6.56 (1,1H), 6.47 (m, 2H), 1.60 (s, 6H).

REFERENCE EXAMPLE 8

2-(3,4-Dichlorophenyloxy)-2-methylpropionic acid

¹H NMR (500, CD₃OD): δ 7.40 (dd, 1H), 7.07 (d, 1H), 6.85 (dd, 1H), 1.60(s, 6H).

REFERENCE EXAMPLE 9

2-(3,5-Dichlorophenyloxy)-2-methylpropionic acid

¹H NMR (500, CD₃OD): δ 7.05 (t, 1H), 6.84 (d, 2H), 1.60 (s, 6H).

REFERENCE EXAMPLE 10

2-(3-Chloro-4-fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 M, CD₃OD): δ 7.16 (t, 1H), 7.05 (dd, 1H), 6.90 (td, 1H),1.57 (s, 6H).

REFERENCE EXAMPLE 11

2-(4-Chloro-3-fluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 7.36 (t, 1H), 6.80 (dd, 1H), 6.74 (dd, 1H),1.60 (s, 6H).

REFERENCE EXAMPLE 12

2-(3,4,5-Trifluorophenyloxy)-2-methylpropionic acid

¹H NMR (500 MHz, CD₃OD): δ 6.68 (dd, 2H), 1.60 (s, 6H).

REFERENCE EXAMPLE 13

2-(2-Pyridyloxy)-2-methylbutanoic acid Step A: Benzyl2-(2-Pyridyloxy)propionate

To a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL ofmethylene chloride was added diethylazodicarboxylate (7.8 mL, 45 mmol)at 0° C. The reaction was allowed to warm to room temperature for 4 h.The resulting mixture was diluted with hexane (100 mL) and concentratedwith 20 g of silica gel. The material was loaded onto a silica gelcolumn, which was eluted with 10% ethyl acetate in hexane to give thetitle compound. ¹H NMR (500 M, CD₃OD): δ 8.00 (dd, 1H), 7.68 (ddd, 1H),7.36-7.28 (m, 5H), 6.94 (dd, 1H), 6.84 (dd, 1H), 5.30 (q, 1H), 5.18 (s,2H), 1.59 (d, 3H). LC-MS: m/e 258 (M+H)⁺ (3.3 min).

Step B: Benzyl 2-(2-Pyridyloxy)-2-methylbutanoate

To a solution of benzyl 2-(2-pyridyloxy)propionate (1.6 g, 6.2 mmol) andethyl iodide (1.5 mL, 25 mmol) in 10 mL of anhydrous tetrahydrofuran at−78° C. was added sodium hexamethyldisilazide (1 M in tetrahydrofuran,9.3 mL, 9.3 mmol) (potassium hexamethyldisilazide in toluene may be usedwith similar results). The reaction was allowed to warm to roomtemperature over 2 h and was partitioned between saturated ammoniumchloride (100 mL) and ethyl acetate (100 mL). The organic layer wasseparated and the aqueous layer extracted with ethyl acetate (2×50 mL).The combined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated to dryness, and the residue was purified byflash column chromatography on silica gel eluted with 10% ethyl acetatein hexane to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.87(dd, 1H), 7.63 (ddd, 1H), 7.27 (m, 3H), 7.18. (m, 2H), 6.85 (dd, 1H),6.74 (dd, 1H), 5.08 (ABq, 2H), 2.13 (m, 1H), 1.94 (m, 1H), 1.65 (s, 3H),0.95 (t, 3H). LC-MS: MS: m/e 286 (M+H)⁺ (3.8 min).

Step C: 2-(2-Pyridyloxy)-2-methylbutanoic Acid

A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol)and 10% palladium on carbon (50 mg) in 50 mL of methanol was degassedand filled with hydrogen using a balloon. After stirring at roomtemperature overnight, the reaction mixture was filtered through CELITEdiatomaceous earth and washed with methanol (20 mL), and the filtratewas concentrated to dryness to give the title compound. ¹H NMR (500 MHz,CD₃OD): δ 8.03 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H),2.14 (m, 1H), 1.94 (m, 1H), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m/e 196(M+H)⁺ (1.8 min).

REFERENCE EXAMPLE 14

2-(2-Pyridyloxy)-2-methylpropionic Acid

The title compound was prepared following the procedures described forReference Example 13 substituting ethyl iodide and sodiumhexamethyldisilazide with methyl iodide and potassiumhexamethyldisilazide respectively at Step B.

¹H NMR (500 MHz, CD₃OD): δ 8.04 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H),6.76 (dd, 1H), 1.66 (s, 6H). LC-MS: m/e 182 (M+H)⁺ (1.5 min).

REFERENCE EXAMPLE 15

2-(3-Pyridyloxy-2-methylpropionic Acid

The title compound was prepared following the procedures described forReference Example 14 substituting 2-hydroxypyridine with3-hydroxypyridine at Step A and ethyl iodide with methyl iodide at StepB. ¹H NMR (500 MHz, CD₃OD): δ 8.21 (d, 1H), 8.19 (dd, 1H), 7.43-7.35 (m,2H), 1.62 (s, 6H). LC-MS: m/e 182 (M+H)⁺ (0.3 min).

REFERENCE EXAMPLE 16

2-(4-Pyridyloxy)-2-methylpropionic Acid Step A:N-Trimethylsilylethoxymethyl-4-pyridone

To a solution of 4-hydroxypyridine (3.0 g, 32 mmol) andtrimethylsilylethoxymethyl chloride (5.5 mL, 32 mmol) in 30 mL ofacetonitrile was added cesium carbonate (11 g, 34 mmol). After stirringat room temperature overnight, the reaction mixture was partitionedbetween brine (100 mL) and ethyl acetate (100 mL). The organic layer wasseparated and aqueous layer extracted with ethyl acetate (3×100 mL). Thecombined extracts were dried over anhydrous sodium sulfate, filtered,and concentrated to dryness to give the title compound contaminated withsome O-alkylated product. ¹H NMR (500 MHz, CD₃OD): δ 7.92 (d, 2H), 6.49(d, 2H), 5.28 (s, 2H), 3.62 (t, 2H), 0.96 (t, 2H), 0.024 (s, 9H).

Step B: Benzyl 2-(4-Pyridyloxy)propionate

To a solution of benzyl lactate (6.0 g, 33 mmol) and N-methyl morpholine(2.7 mL, 33 mmol) in 100 mL of anhydrous methylene chloride at −20° C.was added trifluoromethanesulfonyl anhydride (5.6 mL, 33 mmol). Afterstirring at −20° C. for 1 h, the reaction mixture was diluted with 100mL of hexane and washed with dilute aqueous sodium hydrogen sulfate andbrine/saturated aqueous sodium bicarbonate. The organic layer wasseparated, dried over anhydrous magnesium sulfate, filtered, andconcentrated to dryness, and the residue was purified by flash columnchromatography on silica gel eluted with 10% ether in hexane to givebenzyl 2-trifluoromethanesulfonyloxypropionate (6.4 g), which was usedimmediately for the ensuing reaction. Thus, a mixture ofN-trimethylsilylethoxymethyl-4-pyridone (Step A, 3.4 g, 15 mmol) andbenzyl 2-trifluromethanesulfonyloxypropionate (4.7 g, 15 mmol) washeated at 60° C. overnight. After cooling to room temperature, thereaction mixture was dissolved in methylene chloride and loaded onto asilica gel column, which was eluted with 5% methanol in methylenechloride to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.57 (d,2H), 7.42 (d, 2H), 7.4-7.3 (n, 5H), 5.44 (q, 1H), 5.24 (ABq, 2H), 1.72(d, 3H). LC-MS: m/e 258 (M+H)⁺ (1.8 min).

Step C: 2-(4-Pyridyloxy)-2-methylpropionic acid

The product of Step B (4.5 g, 18 mmol) was converted to the titlecompound following the procedure described on Reference Example 13,Steps B-C substituting benzyl 2-(2-pyridyloxy)propionate and ethyliodide with benzyl 2-(4-pyridyloxy)propionate and methyl iodide at StepB. ¹H NMR (500 MHz, CD₃OD): δ 8.44 (d, 2H), 7.14 (d, 2H), 1.70 (s, 6H).LC-MS: m/e 18(M+H)⁺ (0.28 min).

REFERENCE EXAMPLE 17

2-(2-Methoxyphenyloxy)propenoic Acid Step A: Methyl2-(2-Methoxyphenyloxy)propenoate

To a solution of 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (1.0 g,5.6 mmol) in methylene chloride (10 mL) and methanol (10 mL) at 0° C.was added trimethylsilyldiazomethane (2 M in hexane) until yellow colorpersisted, and the reaction was stirred at room temperature for 15 min.The reaction mixture was concentrated to dryness and azeotroped withtoluene. The residue was dissolved in anhydrous tetrahydrofuran (20 mL),and was added methyl iodide (1.8 mL, 28 mmol) and potassiumhexamethyldisilazide (0.5 M in toluene, 17 mL, 8.5 mmol) at −78° C. Thereaction was allowed to warm to room temperature over 4 h, diluted withethyl acetate (100 mL), washed with saturated ammonium chloride (100 mL)and water (100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give the title compound. ¹H NMR (500 MHz,CD₃OD): δ 7.07 (ddd, 1H), 6.97 (dd, 1H), 6.94 (dd, 1H), 6.85 (ddd, 1H),5.52 (d, 1H), 4.64 (d, 1H), 3.86 (s, 3H), 3.83 (s, 3H). LC-MS: m/e 231(M+Na)⁺ (2.6 min).

Step B: 2-(2-Methoxyphenyloxy)propenoic Acid

To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4mmol) in tetrahydrofuran (30 mL) and water (30 mL was added lithiumhydroxide monohydrate 0.17 g, 4.0 mmol). After stirring at roomtemperature overnight, the reaction was quenched by addition ofconcentrated hydrochloric acid (final pH=2), and the product wasextracted with ethyl acetate (3×100 mL). The combined extracts weredried over anhydrous sodium sulfate, filtered, and concentrated todryness to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 7.42(ddd, 1H), 7.22 (dd, 1H), 7.10 (dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H),4.51 (d, 1H), 3.64 (s, 3H).

REFERENCE EXAMPLE 18

2,2-Dimethyl-3-phenylpropionic acid Step A:1-Phenyl-2-chloro-2-methylpropane

A mixture of 5.92 g (40 mmol) of 1-phenyl-2-hydroxy-2-methylpropane and50 mL of conc. hydrochloric acid was stirred at ice bath temperature for1 h and at RT for 3 h. The reaction mixture was then extracted withether. The organic layer was dried over MgSO₄. Solvent removal gave1-phenyl-2-chloro-2-methylpropane.

Step B: 2,2-Dimethyl-3-phenylpropionic acid

A mixture of 3.36 g (20 mmol) of the above chloride, and 560 mg (23mmol) of magnesium turnings in 20 mL of THF containing 0.01 mL of1,2-dibromoethane was stirred for 4 h at RT. Most of the metal wasdigested. Carbon dioxide from dry ice in a flask connected with a hosewas bubbled for 3 h. The reaction mixture was then stirred overnight atRT and quenched with 1N HCL. This was then extracted with EtOAc. Theorganic phase was dried over MgSO₄. Solvent removal gave a residue,which was partitioned between ether and 2N NaOH. The aqueous layer waswashed with ether then acidified with 2N HCl and extracted with EtOAc.The EtOAc solution was dried over MgSO₄. The solvent was removed invacuo to give the desired 2,2-dimethyl-3-propionic acid as an oil. NMR:1.22 (s; 6H), 2.9 (s, 2H), 7.15-7.34 (m, 5H).

REFERENCE EXAMPLE 19

2-Methyl-3-(4-chlorophenyl)propionic acid

A solution of 3-(4-chlorophenyl)propionic acid (1.85 g, 10 mmol) in 10mL of THF was added to 16 mL of freshly prepared 1.5 M LDA (24 mmol) atdry ice-acetone bath temp. The reaction mixture was stirred 1 hr as itwarmed to −30° C. and 1.6 mL (25 mmol) of methyl iodide was added. Theresulting mixture was stirred at the same temp. for 0.5 h and thestirring was continued at RT overnight. The reaction was quenched with 1N HCl, and diluted with ether. The solution was washed with water, 10%sodium thiosulfate and brine. The organic layer was dried over MgSO₄.Solvent removal gave a mixture of the desired methylated product and thestarting acid. Repetition of the above procedure on this residue gavethe desired 2-methyl-3-(4-chlorophenyl) propionic acid contaminated with˜5% of the starting acid as an oil. NMR: 1.5 (d, 3H), 4.78 (q, 1H). 6.84& 7.26 (2d, 4H).

REFERENCE EXAMPLE 20

2-Methyl-2-(4-trifluoromethylphenyloxy)propionic acid

The title compound was prepared following the same procedure describedfor Reference Example 1. ¹H NMR (500 MHz, CD₃OD): δ 7.56 (d, 2H), 7.00(d, 2H), 1.62 (s, 6H.

REFERENCE EXAMPLE 21

2-Methyl-2-(3-chloro-5-fluorophenyloxy)propionic acid Step A:3-Chloro-5-fluorophenol

To a solution of 1-bromo-3-chloro-5-fluorobenzene (16 g, 76 mmol) in 250mL of anhydrous ether at −78° C. was added tert-butyllithium (1.7 M, 100mL, 170 mmol). After stirring at −78° C. for 1 h, trimethyl borate (20mL, 176 mmol) was added, and the reaction was allowed to warm to roomtemperature overnight. The resulting mixture was cooled to −10° C., andwas added peracetic acid (32% in acetic acid, 35 mL). After stirring at0° C. for 30 min, potassium bisulfite (5 g) was added. After stirring atroom temperature for 30 min, the aqueous layer was separated and theorganic mixture was extracted with 3 M aqueous sodium hydroxide (3×100mL). The aqueous extracts were acidified with concentrated hydrochloricacid (pH=2), and was extracted with ether (3×150 mL). The combined etherextracts were dried over anhydrous magnesium sulfate, filtered andconcentrated to afford the crude phenol, which was azeotroped withheptane (100 mL) to remove traces of acetic acid to give the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 7.51 (br s, 1H), 7.35 (br d, 1H),7.21 (m, 1H).

Step B: 2-Methyl-2-(3-chloro-5-fluorophenyloxy)propionic acid

The title compound was prepared following the procedures described forReference Example 1. ¹H NMR (500 MHz, CD₃OD): δ 7.53 (br s, 1H), 7.36(br d, 1H), 7.20 (m, 1H), 1.24 (s, 6H).

REFERENCE EXAMPLE 22

2-Methyl-2-(3-pyridazinyloxy)propionic acid

The title compound was prepared following the procedures described forReference Example 13 substituting 2-hydroxpyridine with3-hydroxypyridazine at Step A and ethyl iodide with methyl iodide atStep B. ¹H NMR (500 MHz, CD₃OD): δ 7.98 (dd, 1H), 7.45 (dd, 1H), 6.96(dd, 1H), 1.70 (s, 6H).

REFERENCE EXAMPLE 23

2-Methyl-2-(5-chloro-2-pyridyloxy)propionic acid Step A: Ethyl2-Methyl-2-(5-chloro-2-pyridyloxy)propionate

A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77mmol) in 50 mL of acetonitrile was heated at 50° C. overnight. Thevolatile materials were removed by concentrating on a rotary evaporator,and the residue was partitioned between water (100 mL) and ethyl acetate(100 mL). The organic layer was separated and the aqueous layerextracted with ethyl acetate (2×100 mL). The combined organic extractswere dried over anhydrous sodium sulfate, filtered and concentrated todryness, and the residue was purified by flash column chromatography onsilica gel eluted with 5% ethyl acetate in hexane to give the titlecompound. ¹H NMR (500 MHz, CD₃OD): δ 7.99 (d, m), 7.67 (dd, 1H), 6.68(d, 1H), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M+H)⁺(3.41 min).

Step B: 2-Methyl-2-(5-chloro-2-pyridyloxy)propionic Acid

A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate andsodium hydroxide (0.85 g, 21 mmol) in 15 mL of acetonitrile and 15 mL ofwater was heated at 50° C. overnight. The volatile materials wereremoved by concentrating on a rotary evaporator, and the residue waspartitioned between 2 M hydrochloric acid (100 mL) and ether (100 mL).The organic layer was separated and washed with water (2×50 mL), driedover anhydrous magnesium sulfate, filtered and concentrated to drynessto give the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.02 (d, 1H),7.65 (dd, 1H), 6.77 (d, 1H), 1.62 (s, 6H). LC-MS: m/e 216 (M+H)⁺ (2.33min).

REFERENCE EXAMPLE 24

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with5-trifluoromethyl-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ8.38 (br s, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e250 (M+H)⁺ (2.6 min).

REFERENCE EXAMPLE 25

2-Methyl-2-(6-methyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with6-methyl-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 7.51 (t,1H), 6.74 (d, 1H), 6.53 (d, 1H), 2.34 (s, 3H), 1.64 (s, 6H). LC-MS: m/e196 (M+H)⁺ (1.3 min).

REFERENCE EXAMPLE 26

2-Methyl-2-(4,6-dimethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with4,6-dimethyl-2-hydroxpyridine at Step A. LC-MS: m/e 210 (M+H)⁺ (1.17min).

REFERENCE EXAMPLE 27

2-Methyl-2-(3-trifluoromethylphenyloxy)propionic acid

The title compound was prepared following the same procedure describedfor Reference Example 1. ¹H NMR (500 MHz, CD₃OD): δ 7.45 (t, 1H), 7.28(d, 1H), 7.16 (s, 1H), 7.13 (d, 1H), 1.62 (s, 6H).

REFERENCE EXAMPLE 28

2-Methyl-2-(3-cyanophenyloxy)propionic acid

The title compound was prepared following the same procedure describedfor Reference Example 1. ¹H NMR (500 MHz, CD₃OD): δ 7.63 (d, 2H), 6.97(d, 2H), 1.65 (s, 6H).

REFERENCE EXAMPLE 29

2-Methyl-2-(6-chloromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with6-chloro-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 7.64 (t,1H), 6.95 (d, 1H), 6.72 (d, 1H), 1.65 (s, 6H). LC-MS: m/e 216 (M+H)⁺(2.4 min).

REFERENCE EXAMPLE 30

2-Methyl-2-(2-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with2-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 8.53 (d, 2H),7.09 (t, 1H), 1.74 (s, 6H).

REFERENCE EXAMPLE 31

2 Methyl-2-(5-chloro-2-pyrimidyloxy) propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine withS-chloro-2-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 8.55(s, 2H), 1.73 (s, 6H).

REFERENCE EXAMPLE 32

2-Methyl-2-(4-trifluoromethyl-2-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with4-trifluoromethyl-2-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD):δ 8.85 (d, 1H), 7.48 (d, 1H), 1.76 (s, 6H).

REFERENCE EXAMPLE 33

2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with4-trifluoromethyl-2-hydroxpyridine at Step A. ¹H NMR (500 MHz, CD₃OD): δ8.30 (d, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 1.71 (s, 6H).

REFERENCE EXAMPLE 34

2-Methyl-2-(4-pyrimidyloxy) propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with4-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD): δ 8.67 (s, 1H),8.47 (d, 1H), 6.91 (d, 1H), 1.73 (s, 6H).

REFERENCE EXAMPLE 35

2-Methyl-2-(6-trifluoromethyl-4-pyrimidyloxy)propionic Acid

The title compound was prepared following the procedures described forReference Example 23 substituting 5-chloro-2-hydroxpyridine with6-trifluoromethyl-4-hydroxpyrimidine at Step A. ¹H NMR (500 MHz, CD₃OD):δ 8.81 (s, 1H), 7.28 (s, 1H), 1.75 (s, 6H). LC-MS: m/e 251 (M+H)⁺ (2.1min).

REFERENCE EXAMPLE 36

2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid Step A:2-(4-Trifluoromethyl-2-pyridyloxy)propionic acid

To a suspension of lithium lactate (7.8 g, 81 mmol) in 100 mL ofanhydrous dimethylformamide was added sodium hydride (60% dispersion inmineral oil, 3.2 g, 80 mmol). After stirring at room temperature for 30min, 2-chloro-4-trifluromethylpyridine (10 g, 55 mmol) was added, andthe mixture was heated at 100° C. overnight. The reaction was cooled toroom temperature, poured into 500 mL of water, and was washed withhexane (200 mL). The aqueous solution was acidified with concentratedhydrochloric acid (pH>2), and was extracted with ether (2×500 mL). Thecombined extracts were washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated to dryness to give the titlecompound.

Step B: Methyl 2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionate

To a solution of 2-(4-trifluoromethyl-2-pyridyloxy)propionic acid (StepA, 15 g, 55 mol) in 100 mL of methylene chloride and 100 mL of methanolat 0° C. was added trimethylsilyldiazomethane (2 M solution in hexane)until a yellow color persisted. After stirring at room temperature for15 min, the reaction mixture was concentrated to dryness, and theresidue was purified by flash chromatography on silica gel eluted with 0to 10% ethyl acetate in hexane to give methyl2-(4-trifluoromethyl-2-pyridyloxy)propionate, which was used immediatelyfor methylation following the procedure described in Reference Example13, Step B substituting ethyl iodide with methyl iodide. ¹H NMR (500MHz, CD₃OD): δ 8.25 (d, 1H), 7.18 (d, 1H), 7.15 (s, 1H), 3.65 (s, 3H),1.65 (s, 6H).

Step C: 2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid

To a solution of methyl2-methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionate (Step B, 7.5 g, 29mol) in 50 mL of methanol, 50 mL of tetrahydrofuran and 50 mL of waterwas added sodium hydroxide (2.3 g, 57 mmol). After stirring at 50° C.for 5 h, the reaction mixture was partially concentrated, and was added2 M hydrochloric acid to pH>2. The resulting mixture was extracted withethyl acetate (2×200 mL), and the combined extracts were dried overanhydrous sodium sulfate, filtered, and concentrated to dryness toafford the title compound. ¹H NMR (500 MHz, CD₃OD): δ 8.28 (d, 1H), 7.17(d, 1H), 7.05 (s, 1H), 1.70 (s, 6H).

REFERENCE EXAMPLE 37

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedure described inReference Example 36, Step A with 1.5 extra equivalent of sodium hydridesubstituting lithium lactate with hydroxyisobutyric acid and2-chloro-4-trifluoromethylpyridine 2-chloro-5-trifluoromethylpyridine.¹H NMR (500 MHz, CD₃OD): δ 8.38 (br, 1H), 7.94 (dd, 1H), 6.93 (d, 1H),1.69 (s, 6H).

REFERENCE EXAMPLE 38

2(R)-5-Trifluoromethyl-2-pyridyloxy)propionic Acid Step A:2(R)-(5-trifluoromethyl-2-pyridyloxy)propionate

The title compound was prepared following the procedure described inReference Example 14, Step A substituting 2-hydroxypyridine with5-fluoromethyl-2-hydroxypyridine and benzyl lactate with benzyl(S)-lactate. LC-MS: m/e 326 (M+H)⁺ (3.1 min).

Step B: 2(R)-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedure described inReference Example 13, Step C substituting benzyl2-(2-pyridyloxy)-2-methylbutanoate with2(R)-5-trifluoromethyl-2-pyridyloxy)propionate (Step A). ¹H NMR (500 MCD₃OD): δ 8.70 (s, 1H), 7.67 (d, 1H), 6.63 (d, 1H), 5.30 (q, 1H), 1.67(d, 3H).

REFERENCE EXAMPLE 39

2(R)-(5-Trifluoromethyl-2-pyridyloxy)propionic Acid Step A2(R)-(5-trifluoromethyl-2-pyridyloxy)propionate

The title compound was prepared following the procedure described inReference Example 13, Step A substituting 2-hydroxypyridine with5-trifluoromethyl-2-hydroxypyridine and benzyl lactate with benzyl(S)-lactate. LC-MS: m/e 326 (M+H)⁺ (3.1 min).

Step B 2(R)-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

The title compound was prepared following the procedure described inReference Example 13, Step C substituting benzyl2-(2-pyridyloxy)-2-methylbutanoate with2(R)-5-trifluoromethyl-2-pyridyloxy)propionate (Step A). ¹H NMR (500MHz, CD₃OD): δ 8.70 (s, 1H), 7.67 (d, 1H), 6.63 (d, 1H), 5.30 (q, 1H),1.67 (d, 3H).

REFERENCE EXAMPLE 402-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic Acid

Two nitrogen flushed, 12 L 3-necked round bottom flasks, each fittedwith a thermometer and a reflux condenser were charged with KHMDS in THF(0.91 M, 3.52 L each, 3.205 mol, 1.5 eq). The solutions were cooled to−70° C. and stirred magnetically. Ethyl-2-hydroxyisobutyrate (98%) (463mL, 447 g, 3.38 mol) was added to each flask over 30 min, keeping thereaction temperature below −62° C. After 10 min2-chloro-5-trifluormethylpyridine (388 g, 2.14 mol) was added to eachflask in one portion. The cooling bath was removed and the reactionswere allowed to warm to 20° C. overnight (ca 16 hr.). The reactions weremonitored by TLC (silica, 90/10 Hex/EtOAc) and HPLC:

Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and thereactions were refluxed overnight (ca 22 hr). The reactions wereconcentrated together on a rotary evaporator to remove the THF. To theconcentrate was added water (4 L) and the solution extracted withn-heptane (2×4 L). The aqueous layer was added over 10 min to 2N HCl (9L, 18 mol) with stirring. The resulting suspension was aged for 30 min(temperature 30° C.) then filtered. The cake was washed with water (3×2L), and air-dried to a damp tan solid.

The material was dissolved in n-heptane (4 L) at 65° C. IPAc (1 L) andDARCO KB (40 g, 100 mesh) were added. The mixture was stirrer for 15min, filtered through CELITE diatomaceous earth, and the cake washedwith 4:1 heptane/IPAc (3×500 mL). The filtrate was concentrated to ca. 2L affording a white suspension. The slurry was flushed with heptane (2×3L) and concentrated to ca. 3 L. The resulting white suspension wascooled to 0° C. and aged 1 hr. The product was filtered and the cakewashed with cold heptane (1 L) to provide the title compound as whitecrystalline material. HPLC Column: YMC Combiscreen Pro C18, 50×4.6 mm;Mobile phase: A 0.1% TFA in H₂O; B CH₃CN. Gradient 90/10 A/B to 10/90A/B in 4 min. Flow rate: 4 mL/min. Detection: 254 nm. R_(t)2-chloro-5-trifluormethylpyridine 2.1 min. R_(t)2-ethoxy-5-trifluoromethylpyridine 2.9 min. R_(t) Product Ester 3.1 min.R_(t) Final Acid 2.05 min

REFERENCE EXAMPLE 41

2-Methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionic Acid Step A Ethyl2(5-Methylsulfonyl-2-pyridyloxy)propionate

A mixture of ethyl 2-hydroxyisobutyrate (0.41 mL, 3.0 mmol),2,5-bis(methyl sulfonyl) pyridine (J. Heterocycl. Chem. 1985, 22, 1583)(0.70 g, 3.0 mmol) and sodium hydride (60% dispersion in mineral oil,0.14 g, 3.6 mmol) in 30 mL of anhydrous DMF was heated at 80° C.overnight. The reaction mixture was cooled to room temperature, and waspartitioned between saturated aqueous ammonium chloride (200 mL) andether (200 mL). The organic layer was separated and was washed withwater and brine, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness, and the residue was purified by flash columnchromatography on silica gel eluting with 0 to 80% ethyl acetate inhexane to give the title compound as a 1:1 mixture with2-ethoxy-5-methylsulfonylpyridine. LC-MS: m/e 288 (M+H)⁺ (0.70 min).

Step B 2-Methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionic Acid

To a solution of ethyl2-methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionate (Step A, 0.45 g,1.6 mol) in 5 mL MeOH, 10 mL THF and 10 mL water was added sodiumhydroxide (0.19 g, 4.7 mmol). After stirring at room temperature for 3days, the reaction mixture was partially concentrated, and was added 2 Mhydrochloric acid to pH>2. The resulting mixture was extracted withEtOAc (2×20 mL), and the combined extracts were dried over anhydroussodium sulfate, filtered, and concentrated to dryness to afford thetitle compound. ¹H NMR (500 MHz, CD₃OD): δ 8.60 (d, 1H), 8.16 (dd, 1H),7.17 (d, 1H), 3.15 (s, 3H), 1.71 (s, 6H).

REFERENCE EXAMPLE 42

N-{[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1,2-dimethyl]propyl}amine,hydrochloride (Diastereomer α and β Step A: 1-(3-bromophenyl)acetone

To a solution of N-methoxy-N-methylacetamide (10 g, 0.10 mol) in 200 mLof ether at 0° C. was added 3-bromobenzylmagnesium bromide (0.25 M, 200mL, 50 mmol). After stirring at 0° C. for 2 h, the reaction mixture waspartitioned between hexane and saturated aqueous ammonium chloride. Theorganic layer was separated, washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness to give thetitle compound, which was used without further purification. ¹H NMR (500MHz, CD₃OD): δ 7.5-7.1 (m, 4H), 3.78 (s, 2H), 2.19 (s, 3H).

Step B: 3-(3-Bromophenyl)-2-butanone.

To a solution of 3-bromophenylacetone (4.7 g, 22 mmol) in acetonitrile(100 mL) was added methyl iodide (1.4 mL, 22 mmol) and cesium carbonate(14 g, 44 mmol). After stirring at room temperature for 17 h, thereaction mixture was poured into ether (100 mL) and water (100 mL). Theorganic layer was separated and the aqueous layer extracted with ether.The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated to dryness to give the title compound. ¹H NMR(400 MHz, CD₃OD): δ 7.45-7.40 (m, 2H), 7.3-7.2 (m, 2H), 3.87 (q, 1H),2.06 (s, 3H), 1.34 (d, 3H).

Step C: 3-(3-Bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanone

To a solution of 3-(3-bromophenyl)-2-butanone (2.0 g, 8.8 mmol) inmethylene chloride (100 mL) was added 4-chlorobenzyl chloride (1.4 g,8.8 mmol), tetrabutylammonium iodide (0.16 g, 0.44 mmol) and cesiumhydroxide monohydrate (5.9 g, 35 mmol). After stirring at roomtemperature for 3.5 h, the reaction mixture was poured into ethylacetate (100 mL) and water (100 mL). The organic layer was separated andthe aqueous layer extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated to dryness to give the title compound. ¹H NMR (400 MCD₃OD): δ 7.5-7.1 (m, 4H), 7.08 (d, 2H), 6.68 (d, 2H), 3.16 (ABq, 2H),1.98 (s, 3H), 1.42 (s, 3H).

Step D: 3-(3-Bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanol

To a solution of3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanone (1.6 g, 4.6mmol) in methanol (50 mL) was added sodium borohydride (0.26 g, 6.8mmol). After stirring at room temperature for 10 min, the reaction wasquenched by addition of saturated aqueous ammonium chloride (25 mL). Theprecipitate was filtered off and washed with ethyl acetate (25 mL). Theorganic layer of the filtrate was separated, washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated to dryness. Theresidue was purified by flash column chromatography on silica gel elutedwith 5% ethyl acetate in hexane to afford the title compound as twoseparate diastereomers. Faster eluting diastereomer (Diastereomer α) ¹HNMR (400 MHz, CD₃OD): δ 7.63 (s, 1H), 7.42-7.18 (m, 3H), 7.05 (d, 2H),6.80 (d, 2H), 3.92 (q, 1H), 3.19 (d, 1H), 2.86 (d, 1H), 1.13 (s, 3H),1.02 (d, 3H). Slower eluting diastereomer (Diastereomer β) ¹H NMR (400MHz, CD₃OD): 7.40-7.18 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.12 (q,1H), 3.04 (ABq, 2H), 1.17 (s, 3M), 0.84 (d, 3H).

Step E: 2-Azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane

To a solution of 3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanol(fasting eluting diastereomer, 0.90 g, 2.5 mmol) in ethyl acetate (80mL) at 0° C. was added triethyl amine (dried over activated molecularsieves, 0.42 mL. 3.1 mmol) and methanesulfonyl chloride (0.22 mL, 2.8mmol). After stirring at 0° C. for 2 h, the reaction was quenched byaddition of saturated aqueous sodium bicarbonate (10 mL). After stirringat room temperature for 0.5 h, the organic layer was separated, washedwith brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to dryness to give the crude sulfonate, which was usedwithout further purification. Thus, a mixture of the sulfonate andsodium azide (0.83 g, 0.13 mol) in dimethylformamide (5 mL) was heatedat 120° C. for 4 h. The reaction mixture was cooled to room temperatureand was poured into water (40 mL), and the product was extracted withether (2×20 mL). The combined organic extracts were washed with water,dried over magnesium sulfate, filtered and concentrated to dryness, andthe residue was purified on a silica gel column eluting with hexane togive the title compound (Diastereomer α). ¹H NMR (400 MHz, CD₃OD): δ7.43-7.20 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.10 (q, 1H), 3.10 (d,1H), 3.00 (d, 1H), 1.10 (s, 3H), 1.02 (d, 3H).

The slower eluting diastereomer was converted to the other diastereomer(Diastereomer β) of the title compound following the same procedure asdescribed for the faster eluting diastereomer. ¹H NMR (400 MHz, CD₃OD):δ 7.60-7.20 (m, 4H), 7.07 (d, 2H), 6.80 (d, 2H), 3.90 (q, 1H), 3.17 (d,1H), 2.92 (d, 1H), 1.22 (d, 3H), 1.20 (s, 3H).

Step F:2-(N-tert-Butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane

To a solution of2-azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane(Diastereomer α, 0.26 g, 0.68 mmol) in ethyl acetate (5 mL) was addeddi(tert-butyl)dicarbonate (0.18 g, 0.82 mmol) and platinum dioxide(0.025 g). The mixture was degassed and charged with hydrogen with aballoon. After stirring for 1 day, the reaction mixture was filteredthrough CELITE, diatomaceous earth, and the filtrate was concentrated togive diastereomer a of the title compound.

Diastereomer β of2-azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane wasconverted to the Diastereomer β of the title compound following the sameprocedure as described for Diastereomer α.

Step G:N-[3-(4-Chlorophenyl)-2-(3-bromophenyl)-1,2-dimethylpropyl]-aminehydrochloride (Diastereomer α and β)

2-N-tert-Butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane(Diastereomer α, 0.35 g, 0.76 mmol) was treated with 4 M hydrogenchloride in dioxane (5 mL) at room temperature for 2 h. The mixture wasconcentrated to dryness to give Diastereomer α of the title compound.LC-MS: m/e 352 (M+H)⁺ (3.0 min).

Diastereomer β of2-azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane wasconverted to Diastereomer β of the title compound following the sameprocedure as described for Diastereomer α. LC-MS: m/e 352 (M+H)⁺ (3.0min).

REFERENCE EXAMPLE 43

N-{[3-(4-Chlorophenyl)-2-phenyl-2-cyano-1-methyl]propyl}amine,hydrochloride Step A: 4-(4-Chlorophenyl)-3-cyano-3-phenyl-2-butanone

To a solution of α-acetylphenylacetonitrile (1.0 g, 6.3 mmol) inacetonitrile (25 mL) was added 4-chlorobenzyl bromide (1.3 g, 6.3 mmol)and cesium carbonate (8.2 g, 25 mmol). After stirring at roomtemperature for 2 h, the reaction mixture was poured into ethyl acetate(100 mL) and water (100 mL). The organic layer was separated, washedwith brine, dried over magnesium sulfate, filtered, and concentrated todryness, and the residue was purified on a silica gel column elutingwith 1 to 5% ethyl acetate in hexane to give the title compound. ¹H NMR(400 MHz, CD₃OD): δ 7.5-6.9 (m, 9H), 3.56 (d, 1H), 3.37 (d, 1H), 2.22(s, 3H). LC-MS: m/e 306 (M+Na)⁺ (3.0 min).

Step B:N-[4-(4-Chlorophenyl)-3-cyano-3-phenyl-2-butylidene]-2-methylpropane-(S)-sulfinamide.

To a solution of 4-(4-chlorophenyl)-3-cyano-3-phenyl-2-butanone (1.9 g,6.7 mmol) and (S)-2-methylsulfinamide (0.74 g, 6.1 mmol) intetrahydrofuran (25 mL) was added titanium tetraethoxide (4.0 mL, 18mmol). After stirring at 60° C. for 6 h and 75° C. for 18 h, thereaction mixture was poured into a well-stirred brine solution (50 mL).The resulting mixture was filtered through CELITE diatomaceous earth andwashed with ethyl acetate (20 mL), and the filtrate was extracted withethyl acetate (2×50 mL). The combined extracts were dried over anhydroussodium sulfate, filtered, and concentrated to dryness, and the residuewas purified by flash column chromatography on silica gel eluted with 10to 20% ethyl acetate in hexane to give the title compound as a 1:1mixture of diastereomers. LC-MS: m/e 387 (M+H)⁺ (3.6 min).

Step C:N-{[3-(4-Chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-methylpropane-(S)-sulfinamide

To a solution ofN-[4-(4-chlorophenyl)-3-cyano-3-phenyl-2-butylidene]-2-methylpropane-S)-sulfinamide(0.50 g, 1.3 mmol) in methanol (25 mL) at 0° C. was added sodiumborohydride (0.075 g, 1.9 mmol). After stirring for 15 min, the reactionwas quenched by addition of saturated aqueous ammonium chloride (25 mL).The organic layer was separated and the aqueous layer was extracted withethyl acetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to dryness to givethe title compound. LC-MS: m/e 389 (M+H)⁺ (3.4 min).

Step D:N-{[3-(4-Chlorophenyl)-2-cyano-2-phenyl-1-methylpropyl]amine}hydrochloridesalt

N-{[3-(4-Chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-methylpropane-(S)-(sulfinamide(0.55 g, 1.4 mmol) in methanol (20 AL) was added 4 M hydrogen chloridein dioxane (25 mL). After stirring for 30 min, the mixture wasconcentrated to dryness to give the title compound as a mixture ofdiastereomers (α and β). LC-MS: m/e 285 (M+H)⁺ (Major diastereomer. 2.0;Minor diastereomer: 2.1 min).

REFERENCE EXAMPLE 44

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}aminehydrochloride Step A:1-Bromo-3-{[(N-tert-butoxycarbonyl)amino]acetyl}benzene

To a solution of 1-bromo-3-iodobenzene (8.8 mL, 69 mmol) in 200 mL ofether at −78° C. was added tert-butyllithium (1.7 M in pentane, 40 mL,69 mmol). After stirring at −78° C. for 30 min, a solution ofN-(tert-butoxycarbonyl)glycine N′-methoxy-N′-methylamide (5.0 g, 23mmol) in 100 mL of tetrahydrofuran was added. After stirring at −78° C.for 2 h, the reaction was allowed to warm up to 0° C., and was quenchedwith dilute aqueous ammonium chloride (200 mL). The organic layer wasseparated, washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated to dryness, and the residue was purified byflash column chromatography on silica gel eluted with 5-10% ethylacetate in hexane to give the title compound. ¹H NMR (400 MHz, CD₃OD): δ8.12 (s, 1H), 7.97 (d, 1H), 7.80 (d, 1H), 7.43 (t, 1H), 4.50 (s, 2H),1.42 (s, 9H).

Step B:3-(4-Chlorophenyl)-2-(3-bromophenyl)-1-[(N-butoxycarbonyl)amino-2-hydroxy]propane

To a solution of 1-bromo-3-{[(N-tert-butoxycarbonyl)amino]acetyl}benzene(0.65 g, 2.1 mmol) in 25 mL of ether at −78° C. was added4-chlorobenylmagnesium chloride (0.25 M in ether, 21 mL, 5.2 mmol). Thereaction was allowed to warm up to −10° C. over 3.5 h and was quenchedat −10° C. with saturated aqueous ammonium chloride (50 mL). The organiclayer was separated, washed with water, dried over anhydrous magnesiumsulfate, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography on silica gel eluted with 5-10% ethylacetate in hexane to give the title compound. ¹H NMR (400 MHz, CD₃OD): δ7.5-7.1 (m, 4H), 7.10 (d, 2H), 6.92 (d, 2H), 3.55 (d, 2H), 3.40 (d, 2H),3.02 (ABq, 2H), 1.38 (s, 9H).

Step C: N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}aminehydrochloride

To a solution of3-(4-chlorophenyl)-2-(3-bromophenyl)-1-[(N-butoxycarbonyl)amino-2-hydroxy]propane(0.38 g, 0.86 mmol) in ethyl acetate (10 mL) was added 4 M hydrogenchloride in dioxane (20 mL). After stirring for 1 h, the mixture wasconcentrated to dryness to give the title compound. LC-MS: m/e 340(M+H)⁺ (2.8 min).

REFERENCE EXAMPLE 45

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}aminehydrochloride Step A:3-(3-Bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-hydroxy]butane

The title compound was prepared following the same procedure describedfor Reference Example 44, Step A and B substitutingN-(tert-butoxycarbonyl)glycine N′-methoxy-N′-methylamide withN-(tert-butoxycarbonyl)-L-alanine N′-methoxy-N′-methylamide. ¹H NMR (500MHz, CD₃OD): δ 7.5-7.0 (m, 6H), 6.82 (d, 2H), 4.11 (m, 1H), 3.07 (ABq,2H), 1.50 (s, 9H), 0.87 (d, 3H).

Step B:3-(3-Bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-fluoro]butane

To a solution of3-(3-bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-hydroxy]butane(2.0 g, 4.4 mmol) in 15 mL of methylene chloride at −78° C. was added(dimethylamino)sulfur trifluoride (1.1 mL, 8.8 mmol), and the reactionwas allowed to warm up to room temperature over 2.5 h. The reaction wasquenched by carefully transferring to a well-stirred saturated aqueoussodium bicarbonate (50 mL). The mixture was extracted with ether (2×50mL), and the combined extracts were dried over anhydrous magnesiumsulfate, filtered and concentrated to dryness. The residue was purifiedon a silica gel column eluting with 4-20% ethyl acetate in hexane togive the title compound as one major diastereomer and some contaminationof the corresponding dehydration product. ¹H NMR (500 MHz, CD₃OD): δ7.4-7.1 (m, 4H), 7.06 (d, 2H), 6.85 (d, 2H), 4.19 (m, 1H), 3.43 (dd,1H), 3.10 (dd, 1H), 1.50 (s, 9H), 0.93 (d, 3H).

Step C:N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}aminehydrochloride

To a solution of3-(3-bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-fluoro]butane(0.16 g, 0.35 mmol) in ethyl acetate (1 mL) was added 4 M hydrogenchloride in dioxane (4 mL). After stirring for 2 h, the mixture wasconcentrated to dryness to give the title compound. LC-MS: m/e 356(M+H)⁺ (3.1 min).

EXAMPLE 1

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α and β)

To a solution of 2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionicacid (Reference Example 37, 96 mg, 0.38 mmol) in methylene chloride (5mL) was added a drop of DMF and oxalyl chloride (0.067 mL, 0.77 mmol).After stirring at room temperature overnight, the reaction mixture wasconcentrated on a rotary evaporator and dried under vacuum, and theresulting crude acyl chloride was used without further purification.Thus, the crude acyl chloride was suspended in 3 mL of methylenechloride and was added to a suspension ofN-{[2-(3-bromophenyl)-3-(4-chlorophenyl)-1,2-dimethyl]propyl)aminehydrochloride (Reference Example 42, Diastereomer α, 0.10 g, 0.26 mmol)and N-methylmorpholine (0.17 mL, 1.5 mmol) in 3 mL of methylenechloride. After stirring at room temperature for 6 h, the reactionmixture was loaded onto a silica gel column, which was eluted with 10%ethyl acetate to give a pure faster eluting isomer of the title compound(diastereomer α). ¹H NMR (400 MHz, CD₃OD): δ 8.38 (br s, 1H), 8.02 (dd,1H), 7.57 (d, 1H), 7.4-7.0 (m, 4H), 6.98 (d, 2H), 6.42 (d, 2H), 4.60 (m,1H), 3.03 (d, 1H), 2.73 (d, 1H), 1.80 (s, 3H), 1.72 (s, 3H), 0.90 (s,3H), 0.74 (d, 3H). LC-MS: m/e 583 (M+H)⁺ (4.3 min).

Diastereomer β of the title compound was prepared following the sameprocedure as described for Diastereomer α substituting Diastereomer α ofN-{[2-(3-bromophenyl)-3-(4-chlorophenyl)-1,2-dimethyl]propyl}aminehydrochloride with Diastereomer β ofN-{[2-(3-bromophenyl)₃₋₄-chlorophenyl)-1,2-dimethyl]propyl}aminehydrochloride. ¹H NMR (400 MHz, CD₃OD): δ8.28 (br s, 1H), 8.00 (dd, 1H),7.4-6.9 (m, 7H), 6.70 (d, 2H), 4.38 (m, 1H), 3.19 (d, 1H), 2.83 (d, 1H),1.57 (s, 3H), 1.46 (s, 3H), 1.20 (s, 3H), 1.00 (d, 3H). LC-MS: m/e 583(M+H)⁺ (4.4 min).

EXAMPLE 2

N-{[3-(4-Chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Enantiomers A, B, C, D)

To a mixture ofN-([3-(4-chlorophenyl)-2-phenyl-2-cyano-1-methyl]propyl}aminehydrochloride (Reference Example 43, 0.20 g, 0.62 mmol) and2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionic acid (ReferenceExample 37, 0.23 g, 0.93 mmol) in 5 mL methylene chloride was addedN-methylmorpholine (0.41 mL, 3.7 mmol) andtris(pyrrolindinyl)phosphonium hexafluorophosphate (0.49 g, 0.93 mmol).After stirring at room temperature for 1 h, the reaction mixture wasloaded onto a silica gel column eluted with 10-15% ethyl acetate inhexane to give the title compound as one major diastereomer and amixture of the two diastereomers.

The mixture of diastereomers was then separated into four stereoisomersby preparative HPLC, eluting on a Chiralpak AD-H column (2 cm×25 cm)with 8% ethanol in hexane (flow rate 12 mL/min).

Enantiomer A: Analytical HPLC: retention time=7.8 min (Chiralpak ADcolumn, flow rate=0.75 mL/min, 8% ethanol/hexane). ¹H NMR (400 MHz,CD₃OD): δ 8.36 (br s, 1H), 8.02 (dd, 1H), 7.4-7.2 (m, 4H), 7.11 (d, 1H),7.00 (d, 2H), 6.63 (d, 2H), 4.77 (q, 1H), 3.42 (d, 1H), 3.21 (d, 1H),1.82 (s, 3H), 1.78 (s, 3H), 0.96 (d, 3H).

Enantiomer B: Analytical HPLC: retention time=9.0 min (Chiralpak ADcolumn, flow rate=0.75 mL/min, 8% ethanol/hexane). ¹H NMR (400 MHz,CD₃OD): δ 8.36 (br s, 1H), 8.02 (dd, 1H), 7.3-7.0 (m, 6H), 7.00 (d, 1H),6.83 (d, 2H), 4.80 (q, 1H), 3.33 (ABq 2H), 1.56 (s, 3H), 1.42 (s, 3H),1.24 (d, 3H).

Enantiomer C: Analytical HPLC: retention time=10.1 min (Chiralpak ADcolumn, flow rate=0.75 mL/min, 8% ethanol/hexane). ¹H NMR (400 MHz,CD₃OD): δ 8.36 (br s, 1H), 8.03 (dd, 1H), 7.4-7.1 (m, 5H), 7.00 (d, 2H),6.64 (d, 2H), 4.78 (q, 1H), 3.42 (d, 1H), 3.22 (d, 1H), 1.82 (s, 3H),1.78 (s, 3H), 0.95 (d, 3H).

Enantiomer D: Analytical HPLC: retention time=10.4 min (Chiralpak ADcolumn, flow rate=0.75 mL/min, 8% ethanol/hexane). ¹H NMR (400 M,CD₃OD): δ 8.36 (br s, 1H), 8.02 (dd, 1H), 7.3-7.0 (m, 6H), 7.00 (d, 1H),6.84 (d, 2H), 4.79 (q, 1H), 3.33 (ABq 2H), 1.57 (s, 3H), 1.43 (s, 3H),1.24 (d, 3H).

EXAMPLE 3

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide

To a mixture ofN-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}aminehydrochloride (Reference Example 44, 0.35 g, 0.93 mmol) and2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionic acid (ReferenceExample 37, 0.35 g, 1.4 mmol) in 5 mL of methylene chloride was addedN-methylmorpholine (0.62 mL, 5.6 mmol) andtris(pyrrolindinyl)phosphonium hexafluorophosphate (0.73 g, 1.4 mmol).After stirring at room temperature overnight, the reaction mixture wasloaded onto a silica gel column eluted with 15-20% ethyl acetate inhexane to give the title compound. ¹H NMR (400 MHz, CD₃OD): δ 8.24 (brs, 1H), 7.92 (dd, 1H), 7.42 (s, 1H), 7.30 (d, 1H), 7.20 (d, 1H),7.15-7.05 (m, 3H), 7.92-7.85 (m, 3H), 3.76 (d, 2H), 3.42 (d, 2H), 2.98(ABq, 2H), 1.57 (s, 3H), 1.48 (s, 3H). LC-MS: m/e 593 (M+Na)⁺ (4.3 min).

EXAMPLE 4

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide

To a solution of 2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionicacid (Reference Example 37, 0.13 mg, 0.53 mmol) in toluene (2 mL) wasadded thionyl chloride (0.077 mL, 1.1 mmol). After stirring at 50° C.for 1 h, the reaction mixture was concentrated on a rotary evaporatorand dried under vacuum, and the resulting crude acyl chloride was usedwithout further purification. Thus, the crude acyl chloride wassuspended in 3 mL of acetonitrile and was added to a suspension ofN-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}aminehydrochloride (Reference Example 45, 0.15 g, 0.35 mmol) and triethylamine (0.10 mL, 1.4 mmol) in 3 mL of acetonitrile. After stirring atroom temperature for 2 h, the reaction mixture was diluted with ethylacetate (100 mL), washed with dilute aqueous sodium hydroxide, brine,dried over anhydrous magnesium sulfate, filtered and concentrated todryness. The residue was purified on a silica gel column eluting with4-25% ethyl acetate in hexane to give the title compound as one majordiastereomer along with some dehydration product. ¹H NMR (500 MD,CD₃OD): δ 8.27 (d, 1H), 7.98 (dd, 1H), 7.37 (br d, 1H), 7.28 (br s, 1H),7.20 (t, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 7.02 (d, 2H), 6.66 (d, 2H),4.58 (m, 1H), 3.33 (dd, 1H), 2.98 (dd, 1H), 1.80 (s, 3H), 1.77 (s, 3H),0.85 (d, 3H). LC-MS: m/e 587 (M+H)⁺ (4.4 min).

EXAMPLE 5

N-{[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide

A mixture ofN-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Example 4, 0.12 g, 0.22 mmol), sodium cyanide (0.015 g, 0.31 mmol),18-crown-6 (63 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium(50 mg, 0.04 mmol) in 2 mL of dioxane was heated under nitrogen at 100°C. for 5 h. After cooling to room temperature, the volatile materialswere removed under vacuum, and the residue was purified by flash columnchromatography on silica gel eluting with 5 to 50% ethyl acetate inhexane to afford the title compound as one major diastereomer along withtrace amount of the dehydration product. ¹H NMR (500 M, CD₃OD): δ 8.26(d, 1H), 7.98 (dd, 1H), 7.58 (m, 1H), 7.52-7.44 (m, 2H), 7.08 (d, 1H),7.02 (d, 1H), 7.01 (d, 1H), 6.67 (d, 2H), 4.63 (m, 1H), 3.38 (dd, 1H),3.03 (dd, 1H), 1.80 (s, 3H), 1.76 (s, 3H), 0.84 (d, 3H). LC-MS: m/e 534(M+H)⁺ (4.2 min).

EXAMPLE 6

N-{[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α)

The title compound was prepared following the same procedure asdescribed in Example 5 substitutingN-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamidewithN-{[3-(4-chlorophenyl)-2-(3-cynaophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Example 1, Diastereomer α). ¹H NMR (400 MHz, CD₃OD): δ 8.37 (br s, 1H),8.03 (dd, 1H), 7.66-7.46 (m, 4H), 7.09 (d, 1H), 6.98 (d, 1H), 6.42 (d,2H), 4.63 (q, 1H), 3.07 (d, 1H), 2.79 (d, 1H), 1.80 (s, 3H), 1.76 (s,3H), 0.99 (s, 3H), 0.72 (d, 3H). LC-MS: m/e 552 (M+Na)⁺ (4.2 min).

EXAMPLE 7

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α and β) Step A:N-{[2-(5-Trifluoromethyl-2-pyridyloxy)-2-methyl]propionyl-L-alanineMethyl Ester.

To a mixture of L-alanine methyl ester (Aldrich, 5.0 g, 36 mmol) and2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionic acid (ReferenceExample 37, 6.3 g, 25 mmol) in 100 mL of methylene chloride was addedN-methylmorpholine (14 mL, 0.10 mol) and tris(pyrrolindinyl)phosphoniumhexafluorophosphate (20 g, 38 mmol). After stirring at room temperaturefor 4 h, the reaction mixture was diluted with ether (300 mL), washedwith dilute aqueous sodium hydroxide, dried over sodium sulfate,filtered and concentrated to dryness. The residue loaded onto a silicagel column eluted with 15-20% ethyl acetate in hexane to give the titlecompound. ¹H NMR (400 MHz, CD₃OD): δ 8.38 (d, 1H), 7.94 (dd, 1H), 6.99(d, 1H), 4.42 (q, 1H), 3.64 (s, 3H), 1.71 (s, 3H), 1.69 (s, 3H), 1.27(d, 3H).

Step B:N-{[2-(5-Trifluoromethyl-2-pyridyloxy)-2-methyl]propionyl-L-alanineN′-methoxy-N′-methylamide

To a suspension of N-methoxy-N-methylamine hydrochloride (4.4 g, 45mmol) in 100 mL of methylene chloride at 0° C. was addeddimethylaluminum chloride (4.0 mL, 45 mmol). After stirring at roomtemperature for 10 min, a solution ofN-{[2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl]propionyl-L-alaninemethyl ester (7.0 g, 21 mmol) in methylene chloride (100 mL) was added,and the resulting mixture was stirred for 2 h. The reaction mixture wasquenched by pouring into a stirred mixture of 2 M hydrochloric acid (200mL) and ice (200 g). The organic layer was separated and the aqueouslayer extracted with ether (2×100 m)). The combined extracts were washedwith 2 M hydrochloric acid, dilute aqueous sodium hydroxide, water andbrine, dried over anhydrous magnesium sulfate, filtered and concentratedto dryness to give the title compound, which was used without furtherpurification.

Step C:N-[1(S)-3-Bromobenzoyl)ethyl]-2-(6-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide

To a solution of 1-bromo-3-iodobenzene (7.7 mL, 60 mmol) in 100 mL ofether at −78° C. was added tert-butyllithium (1.7 M in pentane, 35 mL,60 mmol). After stirring at −78° C. for 15 min, a solution ofN-{[2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl]propionyl-L-alanineN′-methoxy-N′-methylamide (7.7 g, 21 mmol) in 50 mL of ether was added.After stirring at −78° C. for 30 min, the reaction was quenched withsaturated aqueous ammonium chloride (20 mL), and was allowed to warm upto room temperature. The reaction mixture was partitioned betweensaturated ammonium chloride (200 mL) and ether/hexane (1:1, 200 mL). Theorganic layer was separated, washed with water and brine, dried overanhydrous magnesium sulfate, filtered, and concentrated to dryness, andthe residue was purified by flash column chromatography on silica geleluted with 040% ether in hexane to give the title compound. ¹H NMR (500MHz, CD₃OD): δ 8.2-6.9 (mL 7H), 5.28 (q, 1H), 1.63 (s, 3H), 1.62 (s,3H), 1.27 (d, 3H).

Step D:N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl-propanamide(Diastereomers α and β)

To a solution ofN-[1(S)-3-bromobenzoyl)ethyl]-2-(6-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(6.6 g, 14 mmol) in 50 mL of ether at −10° C. was added4-chlorobenylmagnesium chloride (0.25 M in ether, 125 mL, 31 mmol). Thereaction was allowed to warm up to 0° C. over 2 h and was quenched bypouring into saturated aqueous ammonium chloride (200 mL). The organiclayer was separated and the aqueous layer extracted with ethyl acetate100 mL). The combined organic extracts were dried over anhydrousmagnesium sulfate, filtered, and concentrated to dryness. The residuewas purified by flash column chromatography on silica gel eluted with0-50% ethyl acetate in hexane to give the title compound as a fastereluting diastereomer (Diastereomer α, after recrystallization fromtert-butyl methyl ether and hexane) and a slower eluting diastereomer(Diastereomer β) and mixed fractions containing both diastereomers andrecovered starting material.

Diastereomer α: ¹H NMR (500 MHz, CD₃OD): δ 8.34 (d, 1H), 8.00 (dd, 1H),7.38 (m, 1H), 7.34 (m, 1H), 7.22-7.16 (m, 2H), 7.08 (d, 1H), 7.03 (d,2H), 6.68 (d, 2H), 4.46 (q, 1H), 2.91 (ABq, 2H), 1.82 (s, 3H), 1.78 (s,3H), 0.80 (d, 3H). LC-MS: m/e 585 (M+H)⁺ (4.4 min).

Diastereomer β: ¹H NMR (500 MHz, CD₃OD): δ 8.30 (d, 1H), 7.33 (dd, 1H),7.26 (ddd, 1H), 7.12 (ddd, 1H), 7.09-7.02 (m, 3H), 6.92 (d, 1H), 6.82(d, 2H), 4.46 (q, 1H), 3.07 (ABq, 2H), 1.49 (s, 3H), 1.28 (s, 3H), 1.24(d, 3H). LC-MS: m/e 585 (M+H)⁺ (4.4 min).

EXAMPLE 8

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α)

A mixture ofN-([3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α, Example 7, 1.8 g, 3.1 mmol), sodium cyanide (0.23 g,4.6 mmol), 18-crown-6 (1.2 g, 4.6 mmol) and tetrakis(triphenylphosphine)palladium (1.8 g, 1.6 mmol) in 50 mL of dioxane was heated undernitrogen at 100° C. for 4 h. After cooling to room temperature, thereaction mixture was partitioned between ether (200 mL) and water (200mL). The organic layer was separated and the aqueous layer extractedwith ether (200 mL). The combined extracts were dried over anhydrousmagnesium sulfate, filtered, and concentrated to dryness. The residuewas purified by flash column chromatography on silica gel eluting with 5to 20% ethyl acetate in hexane/methylene chloride (1:1) to afford thetitle compound after recrystallization from ethyl acetate/hexane.Analytically pure sample was prepared by reverse-phase HPLC eluting with50-100% acetonitrile in water (0.1% trifluoroacetic acid in eachsolvent) and recrystallization from ethyl acetate and hexane. ¹H NMR(500 MHz, CD₃OD): δ 8.32 (br s, 1H), 7.98 (dd, 1H), 7.58-7.41 (m, 3H),7.42 (dd, 1H), 7.07 (d, 1H), 7.02 (d, 2H), 6.68 (d, 2H), 4.49 (q, 1H),2.94 (ABq, 2H), 1.80 (s, 3H), 1.77 (s, 3H), 0.78 (d, 3H). LC-MS: m/e 532(M+H)⁺ (4.0 min).

EXAMPLE 9

N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(R)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide(Diastereomer α)

The title compound was prepared following the procedure as described inExample 8 starting form D-alanine methyl ester. LC-MS: m/e 532 (M+H)⁺(4.0 min).

BIOLOGICAL EXAMPLE 1

Cannabinoid Receptor-1 (CB1) Binding Assay.

Binding affinity determination is based on recombinant human CB1receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al,Mol. Pharmacol. 48: 443-450, 1995). Total assay volume is 250 μl (240 μlCB1 receptor membrane solution plus 5 μl test compound solution plus 5μl [3H]CP-55940 solution). Final concentration of [3H]CP-55940 is 0.6nM. Binding buffer contains 50 mM Tris-HCl, pH7.4, 2.5 mM EDTA, 5 mMMgCl₂, 0.5 mg/mL fatty acid free bovine serum albumin and proteaseinhibitors (Cat#P8340, from Sigma). To initiate the binding reaction, 5μl of radioligand solution is added, the mixture is incubated withgentle shaking on a shaker for 1.5 h at 30° C. The binding is terminatedby using 96-well harvester and filtering through GF/C filter presoakedin 0.05% polyethylenimine. The bound radiolabel is quantitated usingscintillation counter. Apparent binding affinities for various compoundsare calculated from IC50 values (DeBlasi et al., Trends Pharmacol Sci10: 227-229, 1989).

The binding assay for CB2 receptor is done similarly with recombinanthuman CB2 receptor expressed in CHO cells.

BIOLOGICAL EXAMPLE 2

Cannabinoid Receptor-1 (CB1) Functional Activity Assay.

The functional activation of CB1 receptor is based on recombinant humanCB1 receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48:443450, 1995). To determine the agonist activity or inverse agonistactivity of any test compound, 50 ul of CB1-CHO cell suspension aremixed with test compound and 70 ul assay buffer containing 0.34 mM3-isobutyl-1-methylxanthine and 5.1 uM of forskolin in 96-well plates.The assay buffer is comprised of Earle's Balanced Salt Solutionsupplemented with 5 mM MgCl₂, 1 mM glutamine, 10 mM HEPES, and 1 mg/mLbovine serum albumin. The mixture is incubated at room temperature for30 minutes, and terminated by adding 30 ul/well of 0.5M HCl. The totalintracellular cAMP level is quantitated using the New England NuclearFlashplate and cAMP radioimmunoassay kit.

To determine the antagonist activity of test compound, the reactionmixture also contains 0.5 nM of the agonist CP55940, and the reversal ofthe CP55940 effect is quantitated. Alternatively, a series of doseresponse curves for CP55940 is performed with increasing concentrationof the test compound in each of the dose response curves.

The functional assay for the CB2 receptor is done similarly withrecombinant human CB2 receptor expressed in CHO cells.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein; R¹ is selectedfrom: (1) aryl, (2) aryl-C₁₋₄alkyl, (3) heteroaryl, (4)heteroaryl-C₁₋₄alkyl, wherein each alkyl is optionally substituted withone to four substituents independently selected from R^(a), and eacharyl and heteroaryl are optionally substituted with one to foursubstituents independently selected from R^(b); R² is selected from: (1)C₁₋₁₀alkyl, (2) C₃₋₁₀cycloalkyl-C₁₋₄alkyl, (3) cycloheteroalkyl, (4)cycloheteroalkyl-C₁₋₄alkyl, (5) aryl, (6) aryl-C₁₋₄alkyl, (7)heteroaryl, and (8) heteroaryl-C₁₋₄alkyl, wherein each alkyl isoptionally substituted with one to four substituents independentlyselected from R^(a), and each cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is optionally substituted with one to four substituentsindependently selected from R^(b); R³ is selected from: (1) hydrogen,and (2) C₁₋₄alkyl, wherein each alkyl is optionally substituted with oneto four substituents independently selected from R^(a); R⁴ is selectedfrom: (1) hydrogen, and (2) C₁₋₄alkyl, wherein each alkyl is optionallysubstituted with one to four substituents independently selected fromR^(a); R⁵ is selected from: (1) C₁₋₁₀alkyl, (2) C₂₋₁₀alkenyl, (3)C₃₋₁₀cycloalkyl, (4) C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, (5)cycloheteroalkyl-C₁₋₁₀alkyl, (6) aryl-C₁₋₁₀alkyl, (7) diaryl-C₁₋₁₀alkyl,(8) aryl-C₂₋₁₀ alkenyl, (9) heteroaryl-C₁₋₁₀alkyl, (10) —OR^(d), (11)—S(O)_(m)R^(d), and (12) —NR^(c)R^(d), wherein alkyl, alkenyl,cycloalkyl, and cycloheteroalkyl are optionally substituted with one tofour substituents independently selected from R^(a) and cycloalkyl,cycloheteroalkyl, aryl and heteroaryl are optionally substituted withone to four substituents independently selected from R^(b), providedthat R⁵ is not —CH═CH—COOH; R⁶ is selected from: (1) C₁₋₄alkyl, (2)C₂₋₄alkenyl, (3) C₂₋₄alkynyl, (4) —OR^(d), (5) halogen, (6) —CN, and (7)—NR^(c)R^(d), wherein alkyl, alkenyl, and alkynyl are optionallysubstituted with one to four substituents independently selected fromR^(a); each R^(a) is independently selected from: (1) —OR^(d), (2)—NR^(c)S(O)_(m)R^(d), (3) halogen, (4) —S(O)_(m)R^(d), (5)—S(O)_(m)NR^(c)R^(d), (6) —NR^(c)R^(d), (7) —C(O)R^(d), (8) —CO₂R^(d),(9) —CN, (10) —C(O)NR^(c)R^(d), (11) —NR^(c)C(O)R^(d), (12)—NR^(c)C(O)OR^(d), (13) —NR^(c)C(O)NR^(c)R^(d), (14) —CF₃, (15) —OCF₃,and (16) cycloheteroalkyl; each R^(b) is independently selected from:(1) R^(a), (2) C₁₋₁₀alkyl, (3) oxo, (4) aryl, (5) arylC₁₋₄alkyl, (6)heteroaryl, and (7) heteroarylC₁₋₄alkyl; R^(c) and R^(d) areindependently selected from: (1) hydrogen, (2) C₁₋₁₀alkyl, (3)C₂₋₁₀alkenyl, (4) cycloalkyl, (5) cycloalkyl-C₁₋₁₀alkyl; (6)cycloheteroalkyl, (7) cycloheteroalkyl-C₁₋₁₀ alkyl; (8) aryl, (9)heteroaryl, (10) aryl-C₁₋₁₀alkyl, and (11) heteroaryl-C₁₋₁₀alkyl, orR^(c) and R^(d) together with the atom(s) to which they are attachedform a heterocyclic ring of 4 to 7 members containing 0-2 additionalheteroatoms independently selected from oxygen, sulfur and N—R^(g), eachR^(c) and R^(d) may be unsubstituted or substituted with one to threesubstituents selected from R^(h); each R^(g) is independently selectedfrom: C₁₋₁₀alkyl, and —C(O)R^(c); each R^(h) is independently selectedfrom: (1) halogen, (2) C₁₋₁₀alkyl, (3) —OC₁₋₄alkyl, (4) —S(O)_(m)C₁₋₄alkyl, (5) —CN, (6) —CF₃, and (7) —OCF₃; and m is selected from 0, 1and
 2. 2. The compound according to claim 1, wherein R⁴ is selectedfrom: (1) hydrogen, and (2) methyl; and pharmaceutically acceptablesalts thereof.
 3. The compound according to claim 2, wherein R⁴ ishydrogen; and pharmaceutically acceptable salts thereof.
 4. The compoundaccording to claim 2, wherein R³ is selected from: hydrogen, methyl andethyl; and pharmaceutically acceptable salts thereof.
 5. The compoundaccording to claim 3, wherein R³ is methyl; and pharmaceuticallyacceptable salts thereof.
 6. The compound according to claim 4, whereinR¹ is selected from: (1) phenyl, (2) phenyl-C₁₋₄alkyl, (3) pyridyl, and(4) pyridyl-C₁₋₄alkyl, wherein each phenyl and pyridyl is optionallysubstituted with one or two substituents selected from halogen, methyl,trifluoromethyl, cyano and methoxy, and each pyridyl is optionallypresent as the N-oxide; and pharmaceutically acceptable salts thereof.7. The compound according to claim 5, wherein R¹ is phenyl,unsubstituted or substituted with a halogen or cyano substituent; andpharmaceutically acceptable salts thereof.
 8. The compound according toclaim 6, wherein R² is selected from: (1) isopropyl, (2) isobutyl, (3)n-propyl, (4) n-butyl, (5) cyclopropylmethyl, (6) cyclobutylmethyl, (7)cyclopentylmethyl, (8) cyclohexylmethyl, (9) phenyl, (10) benzyl, (11)phenylethyl, (12) 3-phenylpropyl, (13) 2-phenylpropyl, and (14)pyridylmethyl, wherein each cycloalkyl, aryl and heteroaryl isoptionally substituted with one or two R^(b) substituents selected fromhalogen, trifluoromethyl, cyano, methoxycarbonyl, and methoxy; andpharmaceutically acceptable salts thereof.
 9. The compound according toclaim 7, wherein R² is 4-chlorobenzyl, and pharmaceutically acceptablesalts thereof.
 10. The compound according to claim 9, wherein R⁶ isselected from: (1) methyl, (2) hydroxyl, (3) halogen, and (4) —CN; andpharmaceutically acceptable salts thereof.
 11. The compound according toclaim 9, wherein R⁵ is selected from: (1) C₁₋₈alkyl, (2) C₂₋₈alkenyl,(3) cycloheteroalkyl-C₁₋₈alkyl, (4) aryl-C₁₋₈alkyl, (5)diaryl-C₁₋₄alkyl, (6) aryl-C₂₋₈alkenyl, (7) heteroaryl-C₁₋₈alkyl, (8)—OR^(d), and (9) —NR^(c)R^(d), wherein each alkyl or alkenyl isoptionally substituted with one or two substituents independentlyselected from R^(a), and each cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is each optionally substituted with one to three substituentsindependently selected from R^(b) and wherein cycloheteroalkyl isselected from pyrrolidinyl, 2H-phthalazinyl, azabicyclo[2.2.1]heptanyl,benzoxapinyl, morpholinyl, piperazinyl, dihydroimidazo[2,1-b]thiazolyl,and piperidinyl; aryl is selected from phenyl and naphthyl; andheteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl,pyrazolyl, triazolyl, benzothiazolyl, benzoxazolinyl, isoxazolyl,indolyl and thiazolyl; and pharmaceutically acceptable salts thereof.12. The compound according to claim 10, wherein R⁵ is selected from: (1)C₁₋₈alkyl substituted with OR^(d) or NR^(c)R^(d), (2) C₂₋₈ alkenylsubstituted with OR^(d) or NR^(c)R^(d), and (3) phenyl-C₁₋₈ alkylwherein phenyl is substituted with one to three R^(b) substitutents; andpharmaceutically acceptable salts thereof.
 13. The compound according toclaim 12, wherein R⁵ is:

and pharmaceutically acceptable salts thereof.
 14. The compoundaccording to claim 1, selected from:N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1R)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-3-[2-(phenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-[2-(4-chlorophenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-methyl-3-[2-(phenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-[1-(4-chlorophenyl)ethyl)urea,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenylbutanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-1-ethyl-cyclobutanecarboxamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-1-phenyl-cyclobutanecarboxamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenyl-butanamide,and pharmaceutically acceptable salts thereof.
 15. A method of treatinga disease mediated by the Cannabinoid-1 receptor comprisingadministration to a patient in need of such treatment of atherapeutically effective amount of a compound according to claim
 1. 16.The method according to claim 15 wherein the disease mediated by theCannabinoid-1 receptor is selected from: psychosis, memory deficit,cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders,cerebral vascular accidents, head trauma, anxiety disorders, stress,epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders,constipation, chronic intestinal pseudo-obstruction, cirrhosis of theliver, asthma, obesity, and other eating disorders associated withexcessive food intake.
 17. The method according to claim 16 wherein thedisease mediated by the Cannabinoid-1 receptor is an eating disorderassociated with excessive food intake.
 18. The method according to claim17 wherein the eating disorder associated with excessive food intake isselected from obesity, bulimia nervosa, and compulsive eating disorders.19. The method according to claim 18 wherein the eating disorderassociated with excessive food intake is obesity.
 20. A method ofpreventing obesity in a person at risk for obesity comprisingadministration to said person of about 0.001 mg to about 100 mg per kgof a compound according to claim
 1. 21. A composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.22-27. (canceled)
 28. The compound according to claim 9, wherein: R⁶ isselected from: (1) methyl, (2) halogen, and (3) —CN; andpharmaceutically acceptable salts thereof.
 29. The compound according toclaim 28, selected from the group consisting of:N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-3-[2-(phenyl)ethyl)urea,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-1-ethyl-cyclobutanecarboxamide,and pharmaceutically acceptable salts thereof.
 30. The compoundaccording to claim 9, wherein R⁶ is hydroxy, and pharmaceuticallyacceptable salts thereof.
 31. The compound according to claim 30,selected from the group consisting of:N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(R)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-[2-(4-chlorophenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-methyl-3-[2-(phenyl)ethyl)urea,1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-3-[1-(4-chlorophenyl)ethyl)urea,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenylbutanamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-1-phenyl-cyclobutanecarboxamide,N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenyl-butanamide,and pharmaceutically acceptable salts thereof.
 32. A method of treatinga disease mediated by the Cannabinoid-1 receptor comprisingadministration to a patient in need of such treatment of a compositionaccording to claim
 21. 33. The method according to claim 32 wherein thedisease mediated by the Cannabinoid-1 receptor is selected from:psychosis, memory deficit, cognitive disorders, migraine, neuropathy,neuro-inflammatory disorders, cerebral vascular accidents, head trauma,anxiety disorders, stress, epilepsy, Parkinson's disease, schizophrenia,substance abuse disorders, constipation, chronic intestinalpseudo-obstruction, cirrhosis of the liver, asthma, obesity, and othereating disorders associated with excessive food intake.
 34. The methodaccording to claim 33 wherein the disease mediated by the Cannabinoid-1receptor is an eating disorder associated with excessive food intake.35. The method according to claim 34 wherein the eating disorderassociated with excessive food intake is selected from obesity, bulimianervosa, and compulsive eating disorders.
 36. The method according toclaim 35 wherein the eating disorder associated with excessive foodintake is obesity.
 37. The compound according to claim 1 which is:

and pharmaceutically acceptable salts thereof.
 38. A compositioncomprising the compound according to claim 37 and a pharmaceuticallyacceptable carrier.